INTRODUCTION

Personalized medicine (PM) is the designing of medical treatment to an individual based

on their individual needs. This method of treatment involves studying the specific
requirements of the patient and providing treatment accordingly. With personalized
medicine strategies, clinicians can offer treatment and tailor prevention tactics according
to the individual’s unique characteristics. Personalized medicine offers treatment by
considering data from many different sources which include genotypes, family dynamics,
environmental exposures, and cultural background. It works on the basis of “providing
the right treatment to the right person at the right time”. In other words, it acts as a
medicinal model that uses an individual’s genetic profile [93] to customize the choice of
prescribing drugs, dose and therapy in terms of prevention, identification and treatment of
diseases. Using up and coming method, one can identify the factors [94] contributing to
the genetic predisposition and the molecular mechanism behind the condition, thus
enabling us to tailor treatment and prevention strategies. Personalized medicine promises
to evolve as a particularly original and attractive topic in the field of medicine and the
health care industries. This concept has the potential to bend and optimise the procedure
of traditional medical by proving to be a more effective, strategized therapeutic treatment
taking into account the patient's various situations and requirements. This type of
treatment rises to power not only in disease treatment, but also in preventing the same.
Health care professionals will be able to conclude as to what to base their treatment
methods on, depending on the specific drug response shown by the individual. With this
system of medication on the rise, there will not have to be any worries of hazardous side
effects repeatedly encountered by the trial and error method of traditional medicine. The
effectiveness of the application of PM relies completely on the availability of ready
diagnostic tools, multiple data sources and the patients who are ready to take part.
However, the aim of personalized medicine is not to devise unique treatment for every
individual, but instead to group people into subpopulations according to responses against
a particular treatment or drug. Revolutions in the medical industry has created an
opportunity to create target specific drugs, and furthermore, to bring this system into
play, through the use of already existing drugs and treatments to create optimal
combination therapies. So far, PM is seen as an attractive ambition by experts and the
healthcare system. It can also improve patient experience and confidence in the system
and shift the aim of medicines from adequate response to accurate prevention. For rapid
advancement and development in this emerging field, it is critical that pharmaceutical
companies invest in newly devised technologies and offer to work in a collaborative
manner with regards to academic research terms. Support from all sectors is required to
fulfil the potential of this possible perfect form of therapy thereby reducing the expenses,
cost and time of drug development.

Personalized v Precision medicine

Many researchers have advocated the incorrect interpretation of the term ‘personalized
medicine’. The terminology for this individualized, patient centric therapy is ever
changing, fitting to the advancements being made in the field. ‘Precision medicine’ is a
similar concept to personalized medicine, which has been used for the past decade.
‘Personalized medicine’ is determining the profile of the patient and then prescribing a
treatment that will be most specific to their needs. [91] Here disease subtypes are
recognized and biomarkers are designed that can identify the patients that are most likely
to benefit from this specific treatment and those who will not. [90] It is commonly
misinterpreted to imply that unique drugs and therapies are created for each and every
individual. ‘Precision medicine’ is a very similar concept but it is currently preferred as
genomics are applied to classify the disease for the individualized treatments. It involves
individualizing therapy based on the molecular level of information as well as other new
types of genotypic and phenotypic information. Another reason for the switch to this term
is the incorporation of ‘big data’ [92] into the process of profiling diseases and patient.
[87]

Personalized Medicine for Diabetes (PMFD)

Diabetes Mellitus is a heterogeneous group of metabolic diseases that arise from the
defects in secretion and action of the hormone insulin [97]. It can occur due to genetic as
well as environmental factors and hence known as a “multifactorial” disease. Type 2
diabetes (T2D) arises from both genetic and environmental factors, which is why the
response to any anti-diabetic medication may vary significantly among individuals [99].
Abnormally increased blood glucose levels due to differences and abnormalities in the
pancreatic β cells often characterize diabetes. As a result of its complexity and life-long
suffering, diabetes increases the risk of premature death and morbidity. Broadly classified
into two forms depending on the source and the type of insulin deformities – Type 1
Diabetes (T1D) and Type 2 Diabetes (T2D). Type I diabetes arises due to insulin
deficiencies as a consequence of immune- mediated depletion of β- cells of the pancreas.
Type II diabetes occur due to insulin resistance and the failure of β- cells of the pancreas.
The world is fronting an epidemic rise in incidences of diabetes mellitus (DM) with more
than 415million patients averaged globally. Recently there has been a surge in the
increase of incidence and prevalence of diabetes mellitus (DM) type 2, termed ‘diabetes
tsunami’ The potential impact of DM on health, health care costs, productivity and life
expectancy in the upcoming years are seen to be colossal. The uniform
‘recommendations’ made by the patient care system seldom takes into account the
individual variation in terms of the complications and responses to pharmacological and
lifestyle interventions. [85] In recent years, a multitude of new therapies for diabetes have
been made available. And out of the currently available options, the most potent approach
to combat this epidemic is – Precision Medicine (PM) [86] According to the US
President’s Council of Advisors on Science and Technology:
“Personalized medicine refers to the tailoring of medical treatment to the individual
characteristics of each patient; [...] the ability to classify individuals into subpopulations
that differ in their susceptibility to a particular disease or their response to a specific
treatment. Preventive or therapeutic interventions can then be concentrated on those who
will benefit, sparing expense and side effects for those who will not.” [95] Personalized
medicine, precision medicine, or Theranostics is a form of medicine that is the tailoring
and designing of medical treatment based on the individual characteristics of each
patient. It separates people into different groups—with medical decisions, practices,
interventions and tailoring products to the individual patient based on their predicted
response or risk of disease. It provides an approach to develop “biomarkers” that can
identify patients that are likely to respond well from a particular treatment from those that
might not fully respond or even develop side effects. In other words, personalized
medicine aims at intervening the target individual’s genome to reverse or to rectify the
defect with maximum benefits and less harm. Personalized medicine rather focuses on
assessing each patient and, with the help of their symptoms, signs and targeted
investigations, to develop a personalized treatment plan. The significant benefit of a
personalized medicine approach is the possibility of earlier diagnosis to prevent or treat
the disease via genetic screening tests. The definition of personalized medicine for
diabetes (PMFD) [98] is the use of the patient’s genetic history to devise strategies in the
aims of preventing, diagnosing, treating, or monitoring their condition. Personalized
medicine represents an approach for defining disease subtypes and biomarkers that can
identify patients who are most likely to benefit from a specific treatment and other
patients who are unlikely to respond or develop other such side effects.

1. The identification of genes and biomarkers for diabetes as well as for other major risk
factors such as obesity.
2. The biomarkers identified are utilised in the allotting of resources required for
prevention or control of the disease itself as well as other phenotypes in high-risk
individuals due to the influence of their genotype.
3. Selection of specialized therapies for affected patients. The selection process is
meticulous and requires the allotment of the best drug, the optimal dosage and diet to be
employed.
4. Measurement of circulating biomarkers of diabetes to monitor and control the response
to prevention or therapy against the disease.
We are entering a new era in which technological advancements such as expanded
computational techniques have enabled us to perform surpass milestones of knowledge
and diagnosis [96] The use of theranostics in diabetes diagnosis is only one part of the
clinical practice. The major issue is tailoring the best-suited treatment and dosage
according to the requirements [Annals and internal medicine]. Evidence based medicine
helps narrow the gap between clinical research and applying it to practice.
This field is fairly complex and vast due to the fact that many factors are taken into
account in building the profiles.
 Tissue specific epigenetics (epigenomics)
 Gene expression (transcriptomics)
 Integration of expression data with environmental and drug exposures that can be
captured on large scale targeted and non-targeted assays of metabolites
(metabolomics)
 Proteins (proteomics)
For a truly personalised approach, we need to:
1. Better understand the clinical phenotypic variations and how they affect the
response.
2. Identify the molecular signals that help improve predictability of these responses.
 3. Ascertain the knowing that the above will lead to a change in existing patient
care.

As of now, the applications of PM have been established in monogenic diseases – the use
of sulfonylureas to treat neonatal diabetes due to mutations in the ATP channel gates
[100] In this review we will provide an introduction to the principles behind PM tools
and strategies as well as how they are applied to the treatment of Diabetes Mellitus. This
includes the applications such as: enhanced prediction of onset and course of diabetes
mellitus, its treatment prioritization and goal setting, recognition of potential
pathophysiologic mechanisms and its complications.

Diabetes and its treatment

Till date the established, reliable facts about this disease are very less, however they
allow us to lay a foundation of basis and aid in the precise diagnosis as much as possible.
The different forms and the causes known to a certain degree are:
Type 1 Diabetes (T1D) - this type results from autoimmune destruction of the islets of the
pancreas and due to various factors, such as genetic susceptibility, immunological
tolerance and environmental factors. It is known to be associated with HLA class I and II
allele variants. [88] Type 2 Diabetes (T2D) - this form of is polygenic and a very
complex bunch. They are a major result of interaction between many genetic and
environmental factors. Importantly, the SNPs (short nucleotide polymorphisms) are
associated with the islet development and glucose sensing abilities as well as, insulin
synthesis, secretion, signalling and resistance. [89] Affects 1 in 11 adults. Gestational
Diabetes Mellitus - the form of hyperglycaemia that first manifest during pregnancy. It
can be attributed to the changes in the genetic loci due to hormonal changes. Apart from
this, the disease is also separated and treated as such on whether they are monogenic or
heterogenic. Managing patients with diabetes is more different than traditional treatment
as they represent a group of very diverse people spanning across all ethnicities, age, body
size and whether they are insulin deficient or resistant. Clinicians will have to take these
factors into account when developing a personalized management plan. The process of
personalizing therapy is viewed as more of an art than science. This is because a lot more
research and designing is done in order to properly target the issue and rectify as much as
possible. Personalized therapy encourages us to consider a patient centered approach and
taking a step back from the protocol usually followed.

Precision Medicine in Oncology

A huge progress in our understanding of oncology and cancer mechanism was made
possible through development of molecular techniques. [101] Availability of such large-
scale molecular techniques like next generation sequencing and microarray techniques for
chromosomal instability, gene regulation or methylation pattern allowed to identify
immense numbers of different genetic mutations in each malignancy. [103] These
analyses allowed establishing optimal genetic features to apply as biomarkers for
optimization of cancer patient treatments. Our existing knowledge of genetic markers of
cancerous cells results from long-term studies that showed mutations as being crucial for
development and progression of such oncogenes including wide array of genetic changes
such as chromosomal aberrations, gene mutations and epigenetic inhibition. DNA copy
number variations provide the major contribution of oncogenesis, where the effect of a
tumour suppressor gene is reduced and that of the tumour inducing genes are enhanced.
Following completion of the human genome project, substantial progress has been made
in idealizing the human epigenome, proteome, and the overall genome, thus enabling a
better understanding of pharmacogenomics and the potential for optimizing health care
for the individual has grown significantly. Personalized medicine has so far mainly
involved the regulated use of genetic or other information about an individual patient to
select or idealize that patient’s preventative and therapeutic care. Molecular analysis in
either the healthy or the cancer patient samples may allow for a greater extent of
personalized medicine than what is currently available and what has been proven so far.
Knowledge and data about a patient’s proteome, genetic, and metabolic profile could be
used to devise medical care to that individual’s needs.[102] A major feature of this
medical model is the development of companion diagnostics, where molecular assays that
measure levels of proteins, genes, or specific mutations are used to offer a specific
therapy for an individual’s condition by analysing disease status, selecting the proper
drugs, medication and diet, and tailoring dosages to that patient’s specific needs.
Accordingly, such methods can be used to predict a patient’s risk factors for a number of
conditions and to tailor individual preventative treatments. Although cancer occurrence
and persistence are increasing at a striking rate, progress in treatment has been slow and
expected to be enhanced, and treatment benefits are measured ranging from weeks to
months. Conventionally, patient care is given by clinicians based on pathological
screening, symptoms of the disease, and history of medications for similar diseases in the
family. Following these developments and advancements in diagnostics and early
detection markers, a number of cancer types can be detected before even the pathological
symptoms have started to develop. These markers are biochemical, epigenetic, genetic,
and proteomic. Various technologies can be used to detect these markers in clinical
samples. Use of more than one marker in the same sample generally increases the
sensitivity and specificity of oncogene detection and helps a clinician to diagnose early
and precisely. This data is of great importance because individualized treatment patterns
can be designed based on the presence and stage of cancer as seen from profiles of
markers. Pathological diagnosis is still of the highest standard in clinical practice;
however, molecular diagnosis with additional information may be different and more
efficient than pathological diagnosis.

Need for PM in cancer

Even though the DNA from different cells are the same, gene being coded in one organ
function and behave differently than those in other organs. In oncology, different tumours
may have the same DNA or the same genetic pattern, but the gene expression pattern is
different in different tumour types, which is again based on the position, source and the
nature of the tumour. Technologies such as gene-expression microarray and next
generation sequencing allow us to examine the gene expression pattern of hundreds and
even thousands of genes at a time and to differentiate a cancerous gene expression profile
from normal profiling. For years together, standard medical care has been aided by
cohort-based studies in which the genetic variations of individuals are not accounted for
and most of the conclusions and theories are based at the population or subpopulation
level. Modern personalized medicine system considers an individual’s genetic makeup
and disease history and the medication history of at least the immediate three generations
before a treatment pattern is generated. This is in contrast to conventional personalized
medicine, in which the offered treatment is based on a patient’s family history, social
circumstances, environmental exposure and lifestyle. Advanced personalized medicine
treatment is based on targeted therapy. In targeted therapy, it is mandatory that the
collected information about the modified pathway and the elements leading to cancer are
available. For example, Herceptin is used in analysing female breast cancer patients who
express higher levels of HER-2 receptors and associated ligands.

The contribution of omics to personalized cancer treatment

The conventional approach to personalized medicine has always been considered a direct
reactive approach, in which a doctor examines a patient, diagnoses and identifies the
disease based on symptoms, and then prescribes drugs accordingly. In contrast, in
modern personalized treatment, a clinician analyses the patient’s genetic background, the
genetic makeup and family history first and then prescribes treatment, thus making it a
more precise treatment. We now know more about genomic variability (copy number
variations, deletions, mutations, single nucleotide polymorphisms, insertions,
transversions) and the relation between these variations and the different cancers. These
relational studies help in determining who is at high risk of developing cancer, and if they
develop, who is at a higher risk of proceeding to higher stages of severity. It is seen and
hoped that cancer genomics focuses to advance personalized medicine through DNA
sequencing techniques and the analysis of oncogenes from patients to find new genetic
variations associated with specific cancers. Devising a comprehensive table of the major
genomic changes in many major types of cancer will support advancements in developing
more effective ways to diagnose, treat, and prevent cancer. Cancer is a disease of the
genomic variations. As more is learned and discovered about specific tumour types, it
enhances and supports the theory that each tumour has its own set of genetic changes and
mutations. Understanding the genetic changes and gene expression profiles that are in
oncogenes is paving way to more effective treatment strategies that are constructed to the
genetic profile of each individual patient’s cancer treatment. At the National Institutes of
Health (NIH), the genetic profiling motive explores information and resources to improve
our understanding of cancer and provides a better vision and concentrates on the
importance of tumour samples in genomic research, and the role of cancer genotypes in
personalized medicine. Hence the need of omics in personalized medicine.

Integrating PM in cancer treatment

The field of personalized medicine is devised to advance in therapeutic strategies for a

single subject individual or a subject population based on data that covers the current and
past physical health conditions and environmental exposure of that individual or group of
individuals. Based on these collected data, cancer has been treated using generalized,
“one size fits all” attempts such as chemotherapy, radiation, and surgical removal of
tumours. These treatments vary widely in efficacy between individuals and often cause
adverse effects to healthy, non carcinogenic organs and tissues. The personalized
medicine approach is identified by individualized treatments tailored to specific tissues,
gene variations, and personal exposure factors relevant to each unique patient of cancer.
Companion diagnostics help identify which treatment methods will be most effective for
a specific patient’s tumour, and novel cell therapies are used to target the cancer with
minimal damage to healthy and unaffected tissues, making the model more effective and
safer and easier to comprehend. A few examples of the applications of precision medicine
include identifying genetic predisposition to a disease or its source, identifying patients
and subpopulations for clinical trials, and identifying individuals that are likely to
respond well to specific targeted therapies. The completion of the Human Genome
Project gave clinicians the ability to examine and frame an individual’s genetic code and
to identify genetic contributions to certain diseases. This notable event changed the
perspective on health from being actively respondent to being preventative. Today,
scientists are working toward obtaining a detailed understanding of the mechanisms and
functioning of the body from multiple omics strategies levels and characterizing how
genetic variabilities are affected by environmental exposures. Together, all of this
information will allow scientists and doctors to better predict how patients will respond to
a certain treatment.

Current state of PM:

1. Acquiring personalized medicine data

In this technique, the multiple omics techniques (genomics, transcriptomics, proteomics,
and metabolomics) are used to characterize an individual’s disease condition are
discussed and the results are concluded. The understanding and characterization and
application of these data as techniques in clinical trial design and treatment selection are
discussed meticulously.
2. Developing a precision medicine therapy
Evolving cancer products, such as organoids, monoclonal antibodies, cancer vaccines,
and CAR T-cells which are also presented from a precision medicine perspective. In this
method, there are also the concepts addressed regarding the evolving federal regulations
for Precision products, in order to ensure their safety, efficacy and the varied responses to
it.[105]
3. Broader consequences of precision medicine
The economic and ethical concerns raised by precision medicine are considered.
Establishing and commercializing PM is complicated from an economical, social and
cultural point-of-view. It very well possibly requires alterations to the contemporary
insurance payer organization. The nature of the field can also be facing a fall from an
ethical perspective, requiring the approval of adequate protections to the privacy,
confidentiality and health of targeted patients, and the effect of such targeted therapies.

ROLE OF BIOMARKERS IN PERSONALIZED TREATMENT

Biomarkers play an important role in medicine and especially in the area of ‘personalized
medicine’. They aid in predicting prognosis and dose selection. They are essential tools
in choosing the appropriate treatment and therapy for the patient. The idea of PM is not
new but the possibility of using this concept has been advanced dude to recent
developments such as the development if large scale biological databases (HGP),
methods for patient characterization (omics) and computational tools for analysis of ‘big
data’. [1] ‘Biomarkers’ are features that can be objectively measured and used as
indicators of normal or pathogenic biological processes, as well as for pharmacological
responses to therapeutic treatment.’ They are broadly classified depending on their
biology, measurement and purpose. [6] Biomarkers are of various types. The mandatory
biomarkers are the fully validated biomarkers. There are others - prognostic biomarkers,
used for malignant conditions, diagnostic biomarkers, significant for autoimmune
diseases , and disease severity biomarkers are used for treating inflammatory responses of
the skin. Prognostic biomarkers help predict the progression of disease,[3] whereas
predictive biomarkers deal with the response to a treatment.[4] Biomarkers are hence
necessary for personalized treatment, for diagnosis, prognosis and selection of targeted
therapies. The main types of biomarkers that play a major role in PM are prognostic and
predictive. Biomarkers are also classified based on the nature, into three types - DNA
biomarkers, DNA tumour biomarkers and other general biomarkers. Apart from testing,
biomarkers are also essential in determining whether the treatment can be delayed. A
large number of biomarkers have recently been identified to elucidate treatment outcome,
and some of them have proven predominantly effective in resolving yet to be understood
or ambiguous clinical trial results. For e.g. In skin cancer [2]
Prognostic biomarkers play a role in dermato-oncology. In melanoma, tumour thickness
is the most important biomarker and expression level of nuclear cell proliferation factor
ki67. [5] Diagnostic biomarkers - the most important class of markers under this are the
screening markers. This is a preliminary testing method that distinguishes the healthy
unaffected individuals, from those who have just been affected and are at the early stage
of the disease. Some of the major biomarkers under this category, are point-of-care tests
(POCT) Rheuma-Chec , the CCPoint biomarker, mutated citrullinated vitmentin
(MCV) (it is a test antiserum), and finally the citrullinated peptides/proteins (anti-CCP
antibodies). A remarkable biomarker is the anti- CCP biomarker, used in screening
individuals for Diabetes and Rheumatoid arthritis. Prognostic biomarkers - these
biomarkers are used to choose the course of a particular treatment which can be offered.
The main class of biomarkers under these categories include : MammaPrint®, a
prognostic biomarker used for breast cancer. This biomarker classifies the risk of
metastasis ah high or low, and help clinicians devise the best individualized therapy for
the patient. MammaPrint® has been approved by the FDA for in vitro diagnostic assays.
Predictive biomarkers - these biomarkers are useful in predicting the response of an
individual, in terms of the efficacy, the safety, and the ultimate aim being assisting the
clinical decision- making process. One such biomarker of this category is the IL28B
gene, which is a strong indicator for the drug response against hepatitis C viral infection.
However this treatment has a disadvantage, that, this is not that effective method with the
non- responding genotype or in some cases, genotypes with the African origin or
ancestry. Some of the above biomarker types have already been approved by the FDA,
while commercialization of the other types has been recommended only after clinical
testing. A recent example for such recommended biomarkers, is the epidermal growth
factor (EGFR) mutation, with patients suffering from earlier stages of non-small-cell lung
cancer, hence elucidating if the tyrosine - kinase inhibitory effect is expressed or not.

Phases of diagnostic biomarker studies

There are four different phases used to study the action mechanism of biomarkers. These
phases are usually fixed. Before any alterations such as a new drug entry in the market
can happen, regulatory approval has to be obtained.[18] Using animal models, the drug
safety, pharmacology and pharmacodynamics are studied. In general, the first three
phases focuses on retrieving information such as the pharmacokinetics, clinical efficiency
and the benefit/ risk if any. The fourth phase purely focuses on the relative effectiveness,
premature death rates, mortality rates and the required dose of the drug. The four phases
are:
Phase I- demonstrative supports had to be established that the diagnostic tests can be
applied to humans. It also has to ensure that the technical properties such as the mode of
application and reproducibility are well studied and understood.
Phase II- this phase is to measure initial rates of sensitivity and specificity by
categorizing the tests on people who are either healthy individuals or those who are
suffering at their initial stages of the disease.
Phase III- this stage is the validation stage. The diagnostic tests followed by the clinical
workup is carried out in a setting which would be the exact same when applied in a later
clinical practice.
Phase IV- this is the final step, and is called as the post- validation stage. This stage is to
measure the possibility of substantial changes in the individual and to track and monitor
the effect of the drugs introduced. The phase system of clinical studies were basically
started orienting towards obtaining medical approval for the diagnostic agents which are
devised for clinical in vivo trials. There are a few extended notions to this technique, that
focuses on the approval principles, and hence these are also referred to as the sub- phases
of biomarker studies. One of these notions consists of three stages of analysis which are :
1) discovery, 2) assay development and validation, 3) retrospective validation. The
discovery phase is carried out using certain high- throughput screening methods and for
most biomarkers, this is achieved through GWAS, and even through whole genome
sequence assays. Expression of clone arrays and DNA profiling are an extensive part of
discovery, in the field of proteomics. These clone arrays consists of thousands of human
recombinant protein for antigen and antibody interactions, on a luminex platform.
However the final product will not be obtained from these recombinant proteins or the
clone arrays. Hence there is a need for the next stage, the assay development and
validation. In this stage, a clinical routine is followed where the identified biomarkers are
subjected to for adaptation in a laboratory setting. The principle of complementary
technique employed in this method, is more reliable and accurate. For various DNA
associated biomarkers, this technique combines the need for reduced bias, better- suited
laboratory features, and the optimal choice of biomarkers needed for genetic
determination. An example in this regard is the proteomic analysis of the technique
ELISA, where the assay of the gene AGR2 in voided urine that is secreted in case of
prostate cancer. The final stage is the retrospective assay. This method tests whether the
results obtained through these high throughput techniques stands good even after an
extended course of application in in vivo trials. The sample sizes used for this study is
larger than the ones used in the initial screening process.

Role of Biomarkers in Diabetes Treatment

Haemoglobin a1c( hba1c)

The use of HbA1c as a diagnostic criterion for diabetes and pre-diabetes was recently
added to the aspects of care by the American Diabetes Association (ADA), under the
recommendations of the International Expert Committee. The committees recognized
several applications of HbA1c, for it to have a higher preference over fasting plasma
glucose levels or glucose level by oral glucose load. HbA1c was seen a s a better
biomarker with better index of assay, has less variability, than that of glucose, when
subjected to over hyperglycaemic conditions. The biomarker-glucose relationship was
better shown after the derived average glucose study. This study considered 500
individuals, and the HbA1c data was retrieved and measured at three months, and the
level of blood glucose was measured. The study was done with a minimum of continuous
two-day monitoring of glucose levels and the test being done for at least three weeks. The
results showed a remarkable relation between the biomarker and the glucose level which
did not differ due to factors of age, sex, race, or the type of diabetes. There is a slight
limitation that, these results restrict the application of these principles as they hinder the
cultural and social beliefs of the public. HbA1c is now a routinely used biomarker for
determination of chronic glycemia in diabetes mellitus, and several meticulous studies
have shown HbA1c to respond to lifestyle (diet, weight loss) and pharmacological
therapy in diabetic patients. The discovery of HbA1c and identifying it as a glycated form
of haemoglobin opened up research areas in diabetes that have been stuck in the pipeline
for about forty years.

Metabolic biomarkers of Diabetes

The term carbonyl stress was introduced fifteen years ago where the relative
glycoxydative and lipoxidative mechanisms of the body was hugely enhanced by
diabetes. The reactive carbonyls in the body modify and alter the biomolecules like the
proteins, lipids, nucleic acids and phospholipids. This leads to enhanced production of
end-glycosylated products. This process causes an overall increase in the blood glucose
level in the body and hence is a factor for the disease persistence. Carbonyl stress acts in
various parts of the body, where in some cases they act as bystanders and mediate the
disease mechanism, and in some cases they can potentially act as biomarkers for the
studies. Biomarkers specific for this condition are found in the blood, the tissues, and the
other bodily fluids. For the sake of saving time and the comfort, we usually go for
biomarker assay in the blood or urine, but current technologies help us in assays of
tissues. This method of study helps us focus on the biomarker that is not based on just
molecular profile, but rather a marker that has functional capabilities. Two examples of
tissue-based biomarkers in the context of diabetes are (a) measures of vascular
dysfunction, which in turn leads to vascular injury, and (b) measurement of auto
fluorescence of skin connective tissue proteins.
The biomarkers from the source of carbonyl stress have many implications:
The carbonyl stress causes endothelial dysfunction, thus becoming the very cause of the
disease, and the other being a surrogate measure that keeps track of the long-term
irreversible glycoxidative damage in the body.
Biomarkers for diabetes and the resultant vascular complications will be sought more
widely, and in affected tissues, not only in the body fluids like serum, plasma, or urine.
Not all the new biomarkers will be “biomolecules”: some will depend upon functional
measures and some on new imaging techniques and hence these are the analytical
biomarkers. The tissue-specific markers are essential in diabetes, since it affects various
organs like eyes, heart etc. to various extents within the same individual. For e.g. the
retina is highly specialized, critical, but very small tissue with the unique attribute to
visualize its microvasculature. The tissue-specific biomarkers, and the use of the
revolutionary “omics”, using blood and urine samples from well characterized and
analysed samples, are likely to yield a generation of new biomarkers in the near future.

Role of Biomarkers in Cancer treatment

PM uses newer techniques of molecular analysis such as genomics, proteomics,

transcriptomics and metabolomics along with predictive modelling to better manage and
predict diseases. Proteomics and metabolomics focus on proteins and metabolic products.
This is because proteins and metabolites are a lot closer to disease phenotype and help
understand the relationship between genotype and phenotype. [12] Recent advancements
in these fields have made it possible to compare the proteome or metabolome from
samples of disease against control samples to recognize the differences between them.
These differences are often noted as biomarkers, they help distinguish between healthy
and disease states with high precision. These biomarkers can be used to improve
molecular diagnosis, prognosis as well as underlying disease mechanisms. Biomarkers
should be readily measurable and accessible such as in body fluids (blood, urine, tear,
saliva etc) [13] Biomarkers also help stratify patients into disease sub types and
determine the severity in case of chronic diseases. Proteomics and metabolomics allow
identification and quantification of the metabolites which in turn can act as biomarkers.
The usual pathways in which new disease biomarkers are developed are: discovery,
verification, validation, clinical evaluation and disease control. Discovery is where the
candidate biomarkers are generated from studies involving a number of patients with
controls, carefully selected. Verification stage involves the selection of promising
patients. Validation is usually very challenging and requires pooling results from all
platforms and cross validating potential biomarkers. [14]. Genetic changes have been a
cause of cancer growth and tumors as well as causing the spread of the same. [17] PM
aims to tailor each therapy specific to the patient and the stage or the type of cancer they
are involved in. In the future genetic tests will help decide which treatments are mostly
likely to work is predicted so the inappropriate treatments can be dismissed. Many of the
treatments are drugs called targeted therapies. Currently treatment for cancer could be a
combination of treatments such as surgery, chemotherapy, radiation therapy etc. but with
precision medicine, information about genetic predispositions and changes in the tumour
will help determine what treatment is more beneficial for the patient.
Biomarkers are the reason for the applying the concept of accurate treatment in oncology.
It is clear that any therapy requires some multitude of personalization to obtain the
desired effect. For targeted therapy, biomarker development involves gene sequencing
such as next generation processes to identify mutations, deletions and arrangements.
Biomarkers of sensitivity and resistance play a major role in the case of targeted
therapies. An example is where oral tyrosine kinase inhibitors are used as biomarkers to
help identify who is more likely to benefit from the treatment. Performing biopsies are
the next steps of treatment. In lung cancer, immunotherapies are seen to be more then
effective but in a mere 20% of patients. For immunotherapy, we must look at the
mutational status and tumour mutational burden that correlates with progression free
survival along with the previous gene sequencing techniques. In order to optimise these
treatments for the rest 80% studies need to be carried out in both genetics and immune
profiling of the various regulatory cells in immune microenvironment to better
understand the process. Critical cells looked at for example are tumour-infiltrating
lymphocytes as they will be helpful in determining the best-suited drugs.
For cancer treatment, a multisystem approach using a large models and markers such as
tumour microenvironment, tumour mutational burden, regulatory T cells and epigenetics
will be required.

Targeted cancer therapies

Molecular targets are responsible for the growth, spread and progression of cancer. In
targeted therapies certain drugs are given to inhibit and interfere with the growth and
spread via blocking the targets.
This therapy is also called ‘molecular targeted therapies’ or ‘precision medicine’.
They differ from chemotherapy as they only act on specific molecular targets that are
associated with cancer and not all dividing cancerous cells. This therapy is deliberately
chosen or designed to interact with their target and not just simply kill them. TT are often
cytostatic which means they block tumour cell proliferation and not completely kill them.
These therapies are currently the focus of anticancer drug development and are a
cornerstone of PM because they utilise information of the patients’ genes and proteins to
prevent, diagnose and treat disease.

A. Identification of targets for targeted cancer therapies

In order to develop targeted therapies, good targets need to be identified, the targets that
play a key role in cancer cell growth and survival.
1. Compare the amounts of individual proteins in cancer cells with those in normal cells.
Proteins that are present in cancer cells are usually potential targets especially if they are
known to be involved in cell growth or survival. E.g. Targeted therapies directed against
HER-2 include – trastuzumab (Herceptin), which has been approved to treat breast, and
stomach cancers where HER-2 overexpression can be seen.
2. Determine whether cancer cells produce mutant or altered proteins that are involved in
cancer progression. E.g. Cell growth signalling protein BRAF, which is present in an
altered, form BRAF V600E in melanoma is targeted by Vemurafenib (zelboraf).
3. Chromosomal abnormalities that are present in cancer cells are identified. These
abnormalities can also result in fusion genes. This is a gene that incorporates sections of 2
different genes that results in a fusion protein, which drives cancer development. These
fusion proteins can also be potential targets. E.g. in leukaemia cells, BCR-ABL fusion
protein promotes growth of leukemic cells. Imatinib mesylate (geelvec) targets this
protein.

B. Developing targeted therapies

Developed in a way that it interferes with the ability of target to promote cancer cell
growth or survival. Many targeted therapies are small molecules or monoclonal
antibodies. They are developed for targets that are located inside cells because they can
easily penetrate. Monoclonal antibodies are usually used for outer cellular reasons due to
their large size. These small molecules are identified via HTS (high throughput
screening). Lead compounds are identified and chemically modified to produce numerous
related versions.

Tumour DNA sequencing in cancer treatment [16]

Cancer is a genetic disease caused by changes in the DNA, which control cell functions,
growth and division. Each person’s cancer has a unique combination of genetic changes
and tumour DNA sequencing to identify these unique DNA changes. Usually the genetic
alterations in the cancer help determine an adequate treatment plan. E.g. mutations in
EGFR gene make cells divide rapidly in lung cancer cells. These patients with this
mutation respond to treatment with drugs called EGFR inhibitors. These mutations can be
identified in a patient via tumour DNA sequencing. TDS is most common for with cancer
types that are susceptible to targeted therapies. Genetic testing is not entirely new and are
done routinely in colorectal and lung cancer. A sample of the tumour is removed and
sometimes even healthy cells. The DNA is isolated with a DNA sequencer to read it and
then the sequence is analysed to determine and locate any genetic alterations that could
be susceptible to certain treatments. The healthy cells are examined to determine if there
are any inherited or germline mutations that increase the risk of cancer and to influence
the treatment decisions. DNA sequencing can either be broad or targeted. Targeted DNA
tests are known as multigene panels and are used most frequently in sequencing tests.
They analyse specific ‘driver’ mutations. Broad DNA sequencing tests analyse large
regions of DNA sequence rather than specific mutations. Whole genome sequencing is
the sequence of entire genome (all of the DNA in cells) is read. Whole exome sequencing
is the sequence of exome (genes) read. Quantitative mRNA expression test used to get
information on what treatments work best for the patient. [22]
Technologies supporting PM

i. CRISPR/Cas technology
Gene editing technology, which allows the insertion, deletion and exchange of DNA
sequences in a controlled environment. This technique is used to create animal models tat
can mimic the genetic changes in cancer patients. These animal models with the same
genetic mutation are studied which help scientists figure out the drug or treatment which
is most likely to benefit the patient.
ii. Cryo-electron Microscopy (Cryo-EM)
This is a special type of transmission EM where the samples are examined at extremely
low temperatures (cryogenic). The proteins and viruses are frozen at this temperature and
made easier for the researchers to accurately study the biological events at the atomic
level. It helps researchers understand the possible results of genetic changes in drug
resistance and response.

Personalized cancer medicine is mainly reliant on molecular profiling of cancer cells.

Defining genetic alterations, along with establishing a precise molecular diagnosis of the
tumour and predicting the course of the disease, prescribing the proper diet for the drug
metabolism, allows granting an individual patient tailored therapy with reagrds to
genomic as well as epigenomic characteristics of the tumour and the individual genome
into which it is incorporated. Recent years have seen a remarkable progress in the basic,
translational and clinical research in cancers. These study models have not only affected
the novel diagnostic approaches but have also significantly impacted “molecular
pharmacogenomics and therapeutics”. As we are moving into the era of personalized
therapies, using precise targets for diagnosis of cancers is important since specific drug
therapies will be targeted against these molecules. With time, our understanding of the
pathological evolution of cancer has improved by a large amount. An important part of
this achievement is due to the understanding of modifications and mutations that occur
within the cancer cells, at a molecular level of study. As the tumours progress and start
developing invasive and parasitic capabilities, these molecular changes are left
unregulated due to inherent biologic properties of the cancer cell. Studies made both in
the in vivo and in vitro conditions have shown that molecular alterations play a
significant role in the tumour progression as well as in the overall survival of cancer cells,
considering the inherited factor, which is the genetic stability. These modifications do
offer certain advantages, as they serve as targets to design novel therapies for cancers.
Studies in the past have managed to show that these molecular markers can assist in early
and accurate diagnosis and predict prognosis in cancers. A promising marker in the
detection of cancer is the presence of high frequency of methylated genes in tumours
which lead to adenocarcinoma. Such beneficial changes are mostly due to changes in the
genetic and epigenetic factors of the genome. Such biomarkers, are considered by
scientists to be based on detection of a panel of molecular alterations, that give us a
recognizable pattern of molecular mutations in the cancer cells which can then be applied
as a “signature” specific for each tumour. Tumours are no longer just diagnosed at the
morphological level. Molecular altercations are being detected by high throughput
technologies and have become an integral part of the diagnostic panel for ultimate benefit
to the patient.this rapid progress in the analysis of biomarkers has led to a so- called
revolution in the field of “omics”. Techniques and principles under the omics include
GWAS, whole genome sequencing, next generation sequencing etc. Molecular alterations
are used for cancer diagnosis occurring at the DNA level. These could be additions,
deletions or substitutions. Recent work have pioneered and aided us in basic translational
level for personalized diagnostic approaches.
Some of the main tumour biomarkers are: [9,10]
 Breast = ER/PR and HER-2/new
 Colorectal = EGFR, KRAS, UGT1A1
 Gastric HER-2/neu, GIST and c-KIT
 Leukaemia/lymphoma = CD20 antigen, CD30, PDGFR, Philadelphia
chromosome(BCR/ABL).
 Melanoma = BRAF
 Lung = ALK, EGFR and KRAS
It has been very difficult to pin point the actual causal genes due to the complexity of the
human genome. Many genes are known to control metabolic processes in human cells
and some mutation or alteration of them can induce diseases. Some genes are involved in
whether or not a medication will be effective and tolerated by the patient. Decoding of
the human genome has tremendously advanced medical research because if scientists are
able to locate the genetic profile of a disease (tumour), it can be more precisely targeted.
Purposeful medications can be given that target the cellular metabolic processes triggered
by gene alterations. These specific genetic traits often only occur in a very few
percentage of people. The therapies tailored to treat such small group of people have
become known as PM, stratified, individualized, tailored medicine. [8]

CEA Biomarker

Few of the cancer biomarkers immediately stand out as superior prognostic or diagnostic
tools, and fewer ones have been validated and approved. CEA is by far the most
effective biomarker for cancer treatment, for the in vivo colorectal cancer targeting.
Colorectal cancer biomarkers have been used for a long time as the molecular level
targets for analytic techniques such as fluorescent intra-operative imaging, targeted
PET/MRI, and selective cytotoxic drug delivery. However, such cancer- specific
biomarkers are used in small numbers on a very small scale because they are rarely
evidence- based. [36] CEA is very smiliar and specific with other commonly used
biomarkers such as the tumour-associated glycoprotein-72 (TAG-72), folate receptor-α
(FRα) and Epithelial growth factor receptor (EGFR). All researches made in this field
have been in vivo clinical trials. The commercialization of this biomarker however was
after a meticulous case study involving 280 patients where the expression of the
biomarker was tested quantitatively in the tissues of these individuals. These CEA
biomarkers were more highly expressed in tumour tissue than in matched normal tissue
almost by 98 percent. Carcinoembryonic antigen is greatly helpful in highly specific
tumour imaging and drug delivery. [37]

Epidermal Growth Factor (EGRF):

The epidermal growth factor receptor (EGFR), is a member of the human epidermal
growth factor receptor (HER 1) family of receptor tyrosine kinases, and represents an
important feature for cancer treatment because its activation triggers necessary
metabolism involved in tumour growth and progression, including those of proliferation,
angiogenesis, invasion, and metastasis.[19] EGFR protein may be detected by
immunological analytic techniques. Significant amounts of EGFR protein may be found
in squamous cells of the developed carcinoma and sometimes in adenocarcinomas.
Increased gene copy number and higher EGFR protein expression rates were considered
as useful biomarkers for evaluating response to therapy using first generation small
molecule EGFR receptor tyrosine kinase inhibitors (TKIs). The evaluative power of high
IHC protein expression is, however, poor, but for EGFR gene amplification, the relation
is stronger. Neither of them are routinely used clinical predictive biomarkers because the
EGFR gene mutations are the best predictive markers with regulatory approval achieved
beforehand. In the presence of any detectable gene mutation, the mutant allele is
amplified with more preference, leading to a relation between EGFR amplification and
mutation. The testing methods of studying the role of EGRF are allele specific and find
only the specific mutations associated with the technology incorporated into it. The
EGRF materials used for the assay of biomarkers have the following considerations.
1) The material has been processed or prepared in such a way that does not involve any
alterations before testing.
2) The materials from the testing process are ensured to have no cross contamination
from other patients.
3) Steps should be taken at regular intervals to enrich tumour cells in the sample for DNA
extraction process. [38]

HER2 Biomarker

Breast cancer is a very common and hazardous disease and is a major health issue
worldwide. In most of the breast cancers, there is over expression of this HER-2
complex. Over expression of this leads to poor prognosis and an aggressive form of the
disease. HER2 can cause breast cancer in a peculiar manner. The extracellular domains of
the complex are shed into the system by a process called as ECD shedding. Now the
process of malignancy arises more because the short extracellular domains are act more
as oncogenes than the actual entire full-length receptor of HER2. The rates of breast
cancer have been have been persistent almost by 45 percent due to elevated levels of
serum HER2 receptors. Thus, sHER2(serum HER2) has been put forward as a promising
biomarker for cancer persistence and for monitoring and tracking the disease status of
patients overexpressing HER2. [29]

Thyroglobulin Biomarker

Thyroid cancer is yet another fateful cancer which occurs commonly worldwide, and
easily occurs in those with iodine deficiency. The measurement of thyroid levels in an
individual, from their tissues and serum is an important criteria in assessing those
suffering from thyroid cancer. Diagnosis of tumors from an unknown origin is made easy
by detection of thyroglobulin in surgical specimens. Thyroglobulin assays are perhaps the
only tests on which the complex mechanisms and features depend on and thereby
produce accurate results.[30]

ROLE OF ALLELIC VARIATIONS IN DRUG METABOLISM

SNP:
Single nucleotide polymorphisms are the single base changes in the DNA. They arise due
to the mistakes or errors during normal DNA replication. The average frequency of the
occurrence of SNP is about 1 in a 1000 nucleotides. There are many sources of SNPs.
Some of these include additions, insertions, deletions, transitions, transversions etc. The
occurrence of these SNPs in humans is a widely studied subject. About 99.9 percent of
the nucleotides are the same. The 0.1 percent changes are what makes an individual
different from another. Amongst these changes, there are newly developed changes in the
DNA termed as the mutations. These mutations can be harmless, harmful or latent
(hidden). [39] There are certain genetic variations in certain alleles that need to be
considered because drugs are devised and metabolized based on these variations. A few
of the genes that contribute as a factor for drug designing are as follows:

Cytochrome P450
The class of cytochrome p450 enzymes have over 50 subclasses of enzymes under it.
They are necessary for ensuring proper metabolism of many drugs and medications. The
two major enzymes under this category are the CYP3A4 and CYP2D6. any change or
alterations in these enzymes give rise to and influence drastic changes in an individual’s
drug response. These responses include the responses even to the commonly prescribed
medicines. Any alterations in these enzymes might inhibit its function, thereby causing
unwanted drug to drug responses and certain adverse effects. [31] There is a huge
limitation in this regard because even though the genotype tests reveal the genetic
polymorphism, inhibiting drugs cannot assure positive results with continued course of
medication.

Polymorphism in the gene:

Cytochrome p450 is encoded by a particular gene. Every individual inherits one allele
called the wild type allele. When this allele is replaced or modified by a new variant
allele, mutation or polymorphism is said to occur. Individuals with two copies of the new
variant allele are termed to be poor metabolizers, whereas those with one of the variant
and one of the wild type re not poor metabolizers, but they have reduced enzyme activity.

Drug interactions:

This is the most important factor to be considered before drug designing because
interactions with the drug only leads to either beneficial outcomes or adverse effects.
Drugs interact with the CYP450 in several ways. Drugs maybe interacted with and
metabolized by one of the enzymes ( the CYP450) or with any of the subclasses or a
combination of them (example CYP1A2, CYP2D6, and CYP3A4). Drugs inhibit or
degrade the enzyme in a fashion that affects the metabolic activity of the drug. The level
of inhibition of the drug depends on the dosage and the ability of the inhibitor to bind to
the enzyme. An example of this phenomenon of the action of zoloft, which is a poor
inhibitor at 50 mg but is a potent inhibitor at concentrations like 200 mg. For drugs like
these, the inhibitory effect occurs almost immediately.

Role of Genetic Variants in the Treatment of Diabetes

Biguanidines

Metformin and phenformin have been discovered as effective drugs possessing guanidine
residues with antibiotic activities. Metformin was identified for its benefits since a long
time ago, but was withdrawn due to the side effect “lactic acidosis”.[20]
The major mode of action of metformin was by inhibiting the release of hepatic glucose.
In addition to this property, metformin also continues to provide slight weight reduction
properties and poses minimum risk of hypoglycemia. Metformin is the drug that is
majorly used to treat newly diagnosed type 2 diabetes mellitus. In 2006, metformin
accounted for 37% of non- insulin drugs offered to patients. As much as their progress in
defining the physiological action of metformin, the actual target of the drug is still not
clear. By far, metformin has been recommended as the initial medication offered to
patients with type 2 diabetes. Additionally, metformin has been found to delay or prevent
the onset of type 2 diabetes in patients with cases or symptoms of prediabetes.[40]

GENES ASSOCIATED WITH BIGUANIDINE TREATMENT

SOLUTE CARRIER FAMILY 22 MEMBER 1 (SLC22A1)

Solute carrier family 22 member 1 (SLC22A1) encodes the gene which is expressed in the
hepatocytes (the OCT1) gene. OCT1 helps in transport of metformin into the liver
(hepatocytes) and subsequent activity. It has been expected that highly polymorphic and
mutated SLC22A1 gene will alter the therapeutic success rate of metformin. The
strain rs622342 variant of SLC22A1 gene was predominantly associated with efficacy and
drug metabolism of metformin. Scientista have been able to conclude that these variants
are significantly associated with lower or considerably higher efficacy of metformin in
glucose tolerance test. [32]

SOLUTE CARRIER FAMILY 47 MEMBER 2 (SLC47A2):

This gene is responsible for the predisposition and deposition of metformin from renal
tubular cells into urine. Hence this is an important factor in controlling diabetes insipidus
too. However this system is limiting, because poor plasma glucose control of metformin
assisted by relative differences in HbA1C level. Studies have highlighted the
pharmacogenomics of metformin considering the long- term and the short - term clinical
trials, that focuses on acute drug responses. Numerous factors contribute to the varied
responses in individuals, including genetic variants and clinically similar drug pathways.
Other factors to consider include ethnicity, study design, patient age, environmental
factors, and clinical end points. [33] The pharmaceutical industry has an interest in
understanding the aided prescribing of metformin as a means to identify novel pathways
of the drug action through which metformin functions that can be ideally used for new
therapies as well as to identify patients likely to benefit from co-treatment with another
anti-diabetic agent. Thus, some members of the pharmaceutical industry may be willing
to contribute stored samples from metformin comparator arms from diabetes clinical
trials.
Sulfonylurea Treatment
Different glucose regulatory mechanisms are brought under control by various targeted
drugs, each kind of treatment specific for a form of diabetes, and type 2 diabetes has
remarkably become controversial when it comes to targeted therapies. The American
diabetes association(ADA) and the European association for the study of diabetes (EASD)
have brought together a coordinating system of choosing ‘specific anti-hyperglycemic
agents”.[21]
According to their terms, these specific agents have the property of :
1. Glycemic effectiveness
2. Side effects including long- term complications.
3. Safety profiling
4. Preference of a drug with regard to an individual.[41]
Sulfonylurea has been used for a considerably longer time for treatment of type 2 diabetes
and has seen to be the first oral drug used for diabetes treatment. They are the first-line of
drugs used for anti- hyperglycemic treatment, when the metformin fails to effectively
treat the condition. Sulfonylurea keeps control of the glucose by stimulating insulin
secretion by inhibiting potassium flux that happens through the potassium channels. One
major disadvantage is that the effects are short- lived in this case and needs repetitive
dosage.
GENES ASSOCIATED WITH SULFONYLUREA METABOLISM
Potassium inwardly-rectifying channel, subfamily J, member 11 ATP-sensitive potassium
channel (KATP) is a transmembrane protein of the hepatocytes usually coded by
potassium inwardly-rectifying channel and subfamily J, member 11 (KCNJ11).
significant amounts of SNPs have been reported for the KCNJ11 gene located on
chromosome 11p15.1. Polymorphisms in KCNJ11 have been identified for development
of diabetes because of its necessary role in insulin secretion. In T2DM patients the rs5210
variant located at 3’ UTR of KCNJ11improves the efficiency of gliclazide. The most
widely studied KCNJ11 gene variant rs5219 (E23K) was significantly associated with the
onset of T2DM in Asian Indian and Chinese populations. However, studies performed on
Caucasian individuals demonstrated for no significant differences in glycated
haemoglobin. Some studies have reported that diabetic patients having KCNJ11 gene
variants respond better to pharmacotherapy with sulfonylurea as compared to insulin or
insulin mediated drugs. [42]

Use of Risk Variants in Personalized Treatment

CYP2D6

The very first pharmacogenomics trait (PGx) was identified by recombinant DNA
technology and it showed polymorphism in the debrisoquine or spartine replacement. The
disorder of the defective - enzyme was identified separately in England and Germany.
The cause of polymorphism was independently due to a dominant allele and a recessive
allele which were named extensive metabolizer and intermediate metabolizer
respectively. As a quanitative PGx trait, the first molecular analysis of a polyallelic
mechanism was done by cloning the CYP2D6 gene.[34] The destructive polymorphic
effects due to the coding of an inactive CYP2D6 gene leads to unstable protein folding,
incorrect gene transcription, and sometimes, complete deletion of the gene itself. Later
on, an ultra- metabolizer stage was identified where there were two to thirteen CYP2D6
duplicated genes. This study in individuals gave rise to abnormal and a non- exponential
(non-uniform) mode of drug responses. This condition was even described as a genetic
bottleneck maybe occurring due to environmental stress. Considering this wide range of
variations, there have been several ‘panels’ set up to study the drug metabolism and the
interactions with the CYP2D6 gene. The thus formed CYP2D6 panel comprises of atleast
25 percent of all the commonly prescribed drugs. Amongst the many variations caused by
this gene, most of them predominantly are adverse effects. One such effect is the parent
drug developing highly toxic effects as a result of reduced metabolic rates in the patients.
Hence a patient with high amounts of CYP2D6 activity is expected to show more adverse
effects. This is so because the parent drug needs an active CYP2D6 metabolism to form
complexes like moieties, for instance morphine. [43]

N-Acetylator Phenotype

This type of polymorphism was originally called the isoniazid acetylation polymorphism.
Unusual drug responses were seen in patients who developed a positive tuberculin test
when treated with prolonged course of isoniazid. The clinical results showed an
unexpectedly higher range of peripheral neuropathy. The root cause for this unsual
response is the inability of the enzyme N-acetyltransferase to remove the parent drug out
of the system. [44] In comparison to fast metabolizers, patients with this defective
genotype were called slow acetylators. This polymorphism is not only occuring in case of
isoniazid, but to a wide range of other drugs which have the ability to show similarity to
the substrates of the N-acetylator phenotype. Decades later, it was identified that the
cause of Mendelian inheritance of isoniazid N-acetylation polymorphism was the NAT2
gene, rather than the NAT1 gene. These studies were conducted using 6-h-plasma level
timepoint studies after a standard dosage of isoniazid. This was the first test result
obtained for drug response, which pertained to genetically determined drug clearance
from the body. [45]
CYP2C19 Polymorphism

CYP2C19 is a very important gene because it involves in the metabolism of atleast four
dozens of the commonly prescribed drugs. The case is similar to that of the other two,
where the extensive metabolic phenotype is dominant over the intermediate metabolizer
phenotype. [46] In this case, most patients develop anti-drug responses (ADR). The
mechanism of this gene is is by catalyzing the bioactivation of clopidogrel which is an
anti-platelet prodrug. Loss-of-function alleles (e.g. CYP2C19*2) impair formation of
active metabolites, resulting in decreased platelet inhibition and increased risk for adverse
cardiovascular events, especially in patients undergoing percutaneous coronary
intervention (PCI) . Therefore, alternative anti-platelet therapy (e.g. prasugrel, ticagrelor)
is now recommended for CYP2C19 PM or IM patients –– if there is no contraindication.
[28]

Coumarin-Associated Gene Polymorphisms

Optimizing warfarin, coumarin and acenocoumarol dosage for anticoagulation is an
oligogenic example of a substantial contribution of several genes –– resulting in rapid vs
slow PK and/or PD of coumarins. CYP2C9 , VKORC1, and CYP4F2 polymorphisms
were independently discovered in candidate-gene studies and then later confirmed in
GWAS . [47]The combination of mutations in the CYP2C9, CYP4F2 and VKORC1
genes explains as much as 35–50% of the patient's total variation in drug response . This
means the remaining genetic impact on coumarin response is derived by contributions of
genes other than these three major genes.[48]

Meglitinides
Meglitinides were introduced in the late 1990s. Similar to SUs, this anti-diabetic drug
class stimulates insulin secretion and usually result into less decrease in HbA1c than
Sulfonylurea. Similar to the Sulfonylureas, the meglitinides act on the potassium channel
too, but at a distinct binding site, to stimulate depolarization and insulin secretion as well
as on voltage-gated calcium channels. Inter-individual variability in response to this drug
class is associated with single nucleotide polymorphism in the transporters SLCO1B1,
OATP1B1, CYP2C9 , CYP2C8 and CYP3A4.[49]

DPP4 Inhibitors/GLP-1 Analogs

This class of anti-diabetic medications includes dipeptidylpeptidase-4 (DPP4) inhibitors
(gliptins) and GLP-1 analogs. DPP4 inhibitors were introduced from Personalized
medicine for type 2 diabetes mellitus. [50] They increase the "incretin effect" by
increasing the blood level of the main incretin hormone, glucagonlike peptide-1 (GLP-1),
in order to induce insulin secretion. GLP-1 analogs exert their action as incretin
mimetics. These medications induce incretin signaling pathway and stimulate insulin
secretion, prevent glucagon secretion, and decrease gastric emptying and appetite.
CTRB1 and CTRB2 genes were related to this group of agents, and both encode the
digestive enzyme chymotrypsin, as an important regulator of the incretin pathway.[51]

CONCLUSION
In this article, we have reviewed, analyzed and ventured into the definitions, concepts,
applications of personalized medicine. Personalized medicine provides an opportunity
and a well-established platform of providing precise, individualized treatment to a
person, thus ensuring maximized results, at the same time, reduce cost, and reduce
significant toxicity that may arise due to the varying drug metabolism.[52] Personalized
medicine is a better evolved, better organized and a higher effective method of treatment,
which gives a clear sense of direction for the decision makers in healthcare. It also
provides an opportunity to enhance the effect and the value of currently existing drugs in
the market and to better their effect, hence it has made the recognition of an individual’s
genotype, and their differences in drug responses, an ideal progress toward standardizing
and optimizing therapies.[53] With this field evolving, we can expect that the stake-
holders can progress to an earlier diagnosis and earlier decision - with regards to various
fields of medicine.[54] Through the advancement of personalized medicine, the patient
satisfaction is targeted. Physicians are evidently inclining to this technique, seeking
maximum foolproof results and reduced effects of trial and error hazards. Regulatory
authorities are benefited the maximum through this evolving procedure.[23] The
implication of PM will require modifications and space for newer techniques in practice
patterns for physicians, clinicians, pharmacists and other health care professionals and for
the retailers and manufacturers with regards to product reimbursement, regulatory
validation, and information sharing with other stakeholders and commercial markets.[55]
Personalized medicine has the future and adequate potential to maximize patient
healthcare, aided by healthcare cost reduction, drug development cost reduction and by
saving time. Remarkable progress and developments in personalized medicine have been
made in the past research areas in the field of personalized medicine in cancer, solely
because of the precise high-throughput 'omics' technologies. [56] These techniques,
specifically genomics, are complementary to each other. PM brings the ability to use
molecular markers that give signal for the disease risks or presence before the clinical
signals and symptoms start to show, and it provides the opportunity to concentrate on
prevention and early diagnosis rather than after the onset of the severe forms, or at
advanced stages of disease.[57] In many fields, the clinical interjections can be life-
saving and hence is a cure for many fatal diseases. In the past decade, adequate
investments have been offered to this type of therapy, in order to learn about the disease
pathology, the creation of new therapeutic targets, and the main goal being preventing
diseases before they start appearing.[58] Over the years, PM has been understood to be
the application of diagnostic tools that targets an individual’s needs, basing their
treatment methods on the selected biomarkers, or the genetic and metabolic
characteristics. Public health committees have become skeptical of the need for offering
priority to a personalized treatment, that is based on the diseased individual rather than a
group of population or sub population. personalized medicine has shown proven
implications for the treatment of non-communicable diseases and diseases that might
have latent mutations in them. By notion, Personalized medicine approaches will help
elucidate and improve disease taxonomy, paving way to more specificity about the
pathogenesis and mechanisms of complex conditions such as heart diseases, cancer and
obesity, with a potential to offer therapeutic interventions that optimize treatment results
of the disease with minimal adverse effects.[59] Personalized medicine in cancer has the
following aims and objectives:
1. Figure out the most effective treatment for the cancer patient.
2. Avoid unnecessary treatment that is less likely to work in the case of specific groups of
patients.
3. Avoid unnecessary side effects, trauma, and risks of breast cancer surgery.
4. Identify people who are most likely to respond to a particular cancer therapy.
5. Develop therapies that target specific tumour cells or cellular pathways.[60]
Worldwide collaborations from different participants offer a wide range of benefits and
applications such as:
1. The wider ability of the doctors to use patient’s genetic and other molecular
information as a part of routine medical care.
2. Chance of incorporate patient’s personal preferences to specialize a treatment plan.
3. Extended survival rate, especially in the case of cancer patients.
4. Improved ability to predict which treatment will work best in a specific patient.
5. Design of new tools for building and analyzing treatment data.
6. A better understanding of the underlying mechanism causing the disease.
7. Reduction in the total cost of treatment.
8. Fewer side effects and avoidance of unnecessary treatment. [24]
PM may also be useful in treating rare and unusual hereditary conditions ensuring
conditions such that the clinical phenotypes may represent and provide a sign for one
condition while molecular or genome level testing may imply a specific mutation. In
these cases of rare diseases, choices and options for diagnosis, treatment, and prevention
are very few and cease to provide maximized results. [61] Hence the call for a
personalized treatment approach. This means personalized medicine implicated in disease
diagnosis, works on the general assumption that improvements can be offered upon
molecular or genetic testing, leading to a more accurate treatment for those with
persistent diseases. A part of the promises of personalized medicine lies on the fact that
this concept can identify and give rise to new novel therapies which can cure diseases
which are rare and those which couldn’t be cured easily before.[62] However, since the
risk of cost the possible type of treatments undertakn are for chorinc diseases that are
prevalent globally. Worldwide, there are immense efforts of scientists being laid forward
to implement personalized medicine on an international scale. It is now quite obvious that
precision medicine has proven to give a paradigm shift in the healthcare approaches and
has crossed milestones in the huge number of populations being treated with this
approach.[63] The growth and the availability of genomic tests and an individualized
treatment is seen and this scenario is expected to advance and continue. The concept of
personalized medicine itself has been appreciated since its introduction in the early
1960’s. [35] In the medical practice, personalized medicine has based measurements of
efficacy, drug response and the proper dosage, solely on the genomic constituents of an
individual. The developments and the advancements of personalized medicine itself is a
multidisciplinary approach.[64] This approach requires co-operation and approval from
several personnel from several fields including the academicians, the scientists, the
political and the socioeconomic committees. [65] Collaborations are being made at a
wide range from the different participants worldwide. The contributions of the
pharmaceutical and the biotechnology companies have been well noted and appreciated.
By offering such collaborations, the different personnel have made the patient data
available to the public and to the concerned departments like the pharmaceutical industry,
biotechnology agencies, universities, government agencies, patient groups and volunteer
subpopulations, information technology companies, and healthcare providers. [66] Hence
the advancements and the progress of personalized medicine determine the future
prospects and the further implications into detecting, controlling and managing diseases
on a large scale. Currently advancing projects focuses on developing a strong foundation
for the same, also ensuring building a strong foundation towards the implications of
personalized medicine.[67] This field also has a stretch of progress in the area of
translational science, which is the transfer of preclinical diagnostic techniques into the
actual valid clinical application. The advancements provided by such translational
techniques tend to incline more towards personalized medicine than the traditional and
conventional methods. The overall aim of such collaborations is to provide specific and
individualized guidelines, and basing everything on the genetic information of the
patient. [68] The entire personalized medicine approach reveals whether the personal
genetic testing contributes significant changes to an individual decision in making
healthy lifestyle choices such as exercising and proper diet habits, along with the
maintenance of a proper and detailed drug medication course, in order to avail a medical
assistance. [25] Without a doubt, the concepts of all conventional and traditional
medicines are inclining towards and demanding a personalized treatment approach. The
increase in the genetic information aided by a well designed bioinformatics approach has
helped personalized medicine bloom into what it is today.[69] All efforts that have been
made have focused on offering maximized benefits to patients, physicians,
biopharmaceutical industries, and the society as a whole. Personalized medicine’s impact
globally is seen to have a large drastic impact, that could revolutionize the way the world
sees diseases and their treatment. With all of the above mentioned, positive feedbacks of
personalized medicine along with its presenting advantages, certain limitations do pose a
challenge to the rising success trends. [70] First case being, not all treatments can be dealt
with a personalized approach. A constant challenge personalized medicine faces in this
regard is the personalization of treatment for common diseases. Common diseases have
wide and numerous genetic variations, which are rarely studied as much enhancement is
being made on complicated ailments such as cancer and metabolic disorders. [71]
Another challenge facing the personalization of common diseases is the fact that
identification of rare genes will end up resulting in millions of rare genes because of the
large population size and tailored treatment will mean developing thousands of
treatments for the same condition. A second limitation of personalized medicine is the
fact that other external factors other than genes contribute to drug response. [72] Diet,
lifestyle, and infections do influence the genetic response to drugs. This implies that,
people may have certain genetic variant but unless they are exposed to a particular
disease, that variant becomes irrelevant. Vice versa, diet or lifestyle of an individual may
alter the response of a genetic variant an individual may possess to targeted treatment,
which may complicate the success of personalized medicine.[73] A third limitation is the
limited support from government and other healthcare organizations. Ideally,
personalized medicine should be advanced across the globe since genetic variants are
manifested in the broad ethnic domain. In the developed countries such as USA and
Europe, personalized medicine have been acknowledged and implemented in health
policies to foster its develop personalized medicine. [74] Other collaborating countries
which are holding behind even in the already existing conventional and traditional
medicine will obviously have limited and very meagre resource toward personalized
medicine. For instance, the currently available data on pharmacogenomics does not give
distinct information pertaining to variations and modifications in drug response across all
human population because the data repositories are completely from the Australian race
and the other resources have not been studied widely. [75] With respect to the healthcare
organizations, human data repositories are lacking in genetic science research areas such
as bioinformatics as well the implication of scientific tools for data management. The
precision medicine movement seeks to integrate environmental, lifestyle, and genetic
information to improve and personalize healthcare. This concept has been profoundly
implicated in fields including oncology and psychiatry. [76] Chemotherapeutic agents
and treatments are selected with concerns regarding the patient safety and health
conditions. Genetic profiles have been identified which predict the necessary therapeutic
dose for opioid analgesia and the amount of heart disease risk reduction a patient will
gain from statins .The national institute has initiated a large-scale analysis of the
biological underpinnings of health outcomes for one million study subjects. One key
objective of precision medicine is an improved understanding of who is at risk for
particular diseases. Such information can serve several important purposes. First, more
accurate risk assessment can refine screening guidelines, which are currently based
primarily on a patient’s age with modification for positive family history and behavioural
or demographic risk factors. [77] Improved evaluation of genetic risks and the risk
variants even in the absence of relevant family history or relevance, can identify
subgroups of the population whose risk for breast cancer or colon cancer would benefit
from initiation of screening at a significantly earlier age than national standards currently
recommend. This knowledge can also motivate early interventions to prevent an
undesired outcome, such as the use of risk-reducing surgery for patients with cancer risk
alleles. Finally, improved risk assessment can empower patients with knowledge about
their future health risks, thereby motivating behavioural changes and careful
consideration of overall life plans. The primary driving force behind PM is clearly the
science. Although genomics has so far had the highest profile, we will see other rapidly
advancing ‘omic’ methodologies, like gut microbiomics and proteomic and metabolomic
signatures in the blood contribute just as powerfully, reflecting as they do individual diet,
environment and past treatments. [34] However biomedical science advances need to be
integrated into clinical practice, both at the clinical trial stage and in routine care. Many
companies now routinely profile patients ‘omically’ prior to admitting them to clinical
trials, either as inclusion criteria or as a basis for retrospective analysis when responses
vary. Corporate officials have just published a call for genomic medicine to be firmly
embedded in the National Health Service Greater precision will also come via
increasingly sophisticated medical images, analysed by advanced algorithms. The
application of MRI into diagnosis incorporation and treatment choice in treating prostrate
cancer is a particularly enthralling example, replacing random biopsies with an accurate
picture of the pattern of lesions in an individual’s prostate. Our PM future will
undoubtedly be ‘unevenly distributed’ for some time to come, both in terms of diseases
and geography. [78] Genomic and proteomic profiling of cancer is now quite well
established in major cancer centres, although we will see many new discoveries as we
apply whole genome sequencing to more and more tumours. Likewise the early use of
exome sequencing and whole genome sequencing to rare diseases is becoming standard
in many places. It can sharply curtail the typical ‘diagnostic odyssey’ (from one specialist
to another) for many rare disease patients, providing an unambiguous diagnosis,
sometimes leading to an immediate treatment, but at least an end to uncertainty. [79]

Arrival in other disease areas will be more protracted. In diabetes, monogenic forms of
the disease are already addressed by genomically guided PM; Type 1 diabetes seems
most likely to be next, although patients seem to vary widely in the number and nature of
the dozens of genes now known to be involved in causation of the disease. Type 2 is
likely to be last, with a plethora of potential contributing factors, with the patient’s
genomic predisposition triggered by epigenomic or other factors of the metabolic signal
mediated syndrome that seems to be the major cause for so many age driven chronic
ailments. [80] However some chronic diseases are already seeing the impact of PM. In
asthma and severe cases of obstructive pulmonary disease, doctors are distinguishing
patients with eosinophilic airway inflammation needing more persuasive treatment and
monitoring; in heart congestions, a panel of proteome related tests promises a similar
outstanding results. While the cost of PM tests will continue to drop, the more
sophisticated will clearly not be affordable everywhere on the planet. Many countries are
investing to some extent in genomics, but the less stable collaborators will probably need
to hold on until the findings are shifted into inexpensive gene chips and blood tests before
PM can make its impact in their health systems. [26] Today, with the understanding of
various biomarkers and advanced therapies like the chemotherapy, radiotherapy, and the
biomarker profiles constructed with the basis of genetic profiling techniques, the genetic
drift that drives an individual disease, the failure in the medications, and the preventive
therapies for the same.[81] Finally this approach will entail science driven combination
therapies within and across biomarkers functions and pathways to develop new
medications for biomarker-selected patient populations, with the aim to considerably
improve patient outcomes. After the human genome has been decoded, clinicians are
already able to treat some diseases with much success using such personalized medicine
approaches. Research and developmental efforts in other fields of medication have come
a long way in recent past, so further therapies are likely to be made available soon.[82]
The greatest advancements in PM so far have been made in advanced fields such as
chemotherapeutic medications for example, for breast cancer, lung tumours and
malignant tumors. In no other significant field of medicine has such differentiation
progressed as far as seen in oncology. This development is seen to fall in line with recent
findings in the field. A molecular diagnostic test that simply requires a blood sample can
replace invasive and uncomfortable tissue biopsies. So a multi-gene expression test might
help. Diagnostic tests have shown that personalized medicine better helps in treating
cases of infertility by not just offering assisted reproduction, but also by preserving the
genetic and hereditary characteristics, and thereby improving the quality of life. [83]
Even a small subset of patients who respond well to such treatment may possess chances
to provide continued efficacy in response to treatment and hence can be considered for an
increase in the success rate. Achieving this through personalized medicine needs a few
requirements that need to be met. Medicines must be tested against several targets at a
time simultaneously and obtain particular combinations of target entities. Considering all
these aspects and approaches to personalized medicine. [84] Personalized medicine
promises to evolve as a particularly novel and exiting topic in the field of medicine and
the health care industries. [27] This concept has the potential to transform the procedure
of traditional medical by providing effective, strategized therapeutic treatments based on
the genomic, epigenomic, metabolomic and proteomic profile of an individual, as well as,
considering and remembering to preserve a patient's personal situation and requirements.

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