Lecture 19

Genetics of Cancer

A cancer is a type of neoplasm.

What is a neoplasm?
A neoplasm can be defined as a disorder of cell
growth that is triggered by a series of
acquired mutations affecting a single cell
and its clonal progeny. the causative
mutations give the neoplastic cells a
survival and growth advantage, resulting in
excessive proliferation that is independent
of physiologic growth signals (autonomous).

Robbins and Cotran: Pathologic Basis of

Disease 9th Edition, 2015

What is Cancer?
Not all neoplasms/tumors are cancerous
Benign tumors aren't cancerous.
They can often be removed, and, in
most cases, they do not come back.
Cells in benign tumors do not spread
to other parts of the body.
Malignant tumors are cancerous.
Cells in these tumors can invade
nearby tissues and spread to other
parts of the body. The spread of
cancer from one part of the body to
another is called metastasis.
Some cancers do not form solid tumors.
For example, leukemia is a cancer of the
bone marrow and blood, that are often
referred to as liquid tumors.
http://www.cancer.gov/cancertopics/cancerlibrary/what-is-

Tumor: abnormal accumulation of cells not serving a

physiological function

n tumor: NOT cancer, do not invade locally or travel distantly

nant tumor: Cancer, invade locally, and may travel to distant sites (not a

Metastasis: Process whereby cells leave a primary tumor and travel

through the bloodstream or lymphatic system to a new location
(distant sites).

most cancer deaths are due to metastatic disease

cancers have a predilection for certain organ sites
seed & soil hypothesis
metastatic cells can remain dormant, then re-emerge later

Most common sties of metastasis are liver, lung, and bone

ancers are typically diagnosed through pathological analysis

Biopsy is obtained
Tissue is fixed (usually formaldehyde) processed to
remove water, paraffin is infused, slices (sections) are
cut
Hematoxylin (stains nuclei blue) and eosin (stains
cytoplasm pink) are most commonly used to visualize
cellular architecture

What do pathologists look for when analyzing biopsies?

In general, a loss of differentiation

Differences in arrangements of cells, i.e.
single layered epithelium becomes
multilayered
Cell shape changes, nuclear to cytoplasm
ratio changes
Morphology of the nucleus and/or chromatin
changes
Increase in frequency of mitotic cells
Grading depends on extent of differences
from normal
Boundaries are important, have cells crossed

https://visualsonline.cancer.gov/details.cfm?imageid=2512

What is Cancer?: Major Cancer Categories/Types

Carcinoma - cancer that begins in epithelial cells (of the skin that line or cover
internal organs). There are subtypes of carcinoma, including adenocarcinoma,
which is a carcinoma of glandular origin in epithelial tissue. Most breast, prostate
and colon cancers are adenocarcinomas
Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or
other connective or supportive tissue.
Leukemia - cancer that starts in blood-forming tissue such as the bone marrow
and causes large numbers of abnormal blood cells to be produced and enter the
blood.
Lymphoma and myeloma - cancers that begin in the cells of the
immune system.
Central nervous system cancers - cancers that begin in the tissues of the
brain and spinal cord.
http://www.cancer.gov/cancertopics/cancerlibrary/whatis-cancer

Estimated Cancer Deaths in the US in 2013

For many (perhaps majority) of cancers we do not

know the etiological factors

Cancer epidemiology: Role of

environment: diet? infectious agents?

Key attributes of cancer cells

They grow (biosynthesize) when they should not, aided by a

metabolism shifted from oxidative phosphorylation toward
aerobic glycolysis.
They go through the cell-division cycle when they should
not.
They escape from their home tissues (that is, they are
invasive) and survive and proliferate in foreign sites (that is,
they metastasize).
They have abnormal stress responses, enabling them to
survive and continue dividing in conditions of stress that
would arrest or kill normal cells, and they are less prone
than normal cells to commit suicide by apoptosis.
They are genetically and epigenetically unstable.
They escape replicative cell senescence, either by
producing telomerase or by acquiring another way of
stabilizing their telomeres.

How do cells acquire these attributes?

Cancer is a disease of DNA/chromatin alterations:

both genetic and epigenetic changes occur
that confer new attributes to cells and contribute
to the evolution of a malignant phenotype

Cancer: failure to regulate cell number, involves

increased cell division AND decreased cell death
(and other changes!)
Evidence that cancer is a genetic disease

DNA damaging agents increase risk for cancer

Recurrent chromosomal abnormalities (some blood
cancers are associated with chromosomal
translocations)
Chronic myeloid leukemia: 90%
of patients have reciprocal 9:22
translocation
BCR-ABL is a tyrosine kinase
that is the cause of CML
Gleevec is a drug that inhibits
this kinase and is curative in
most cases

Two categories of cancers: hereditary vs. sporadic

Both are involve genetic changes

In hereditary, cancer risk is transmitted through germline
Sporadic is not transmitted to offspring
Hereditary cases currently account for 5-10 of all cases
Inheritance of a familial cancer allele increases risk, does
not always lead to disease

ample: Breast-ovarian cancer syndrome 1 is associated with a mutant BRCA1 ge

Example: Retinoblastoma, rare childhood eye tumor

Inheritance of mutant gene on Chromosome 13 greatly increases risk
Bilateral tumors often occur in patients with mutation

Knudsons two hit hypothesis for

retinoblastoma; there must be a recessive gene
that, in its wild type form, prevents retinal
cancers.
Sporadic

Familial

Oncogenes and tumor suppressor genes

Oncogenes: dominant-acting stimulatory genes that
promote cancer, usually by stimulating cell division
Proto-oncogenes: responsible for basic cellular
functions in normal cells; when mutated, they become
oncogenes.
Tumor-suppressor genes: recessive-acting inhibitory
genes that generally slow or block cell division

Knudsons two hit hypothesis for

retinoblastoma; there must be a recessive gene
that, in its wild type form, prevents retinal
cancers.
Sporadic

Familial

How were oncogenes first discovered?

Rous sacroma virus (RSV), early 20th century, retrovirus
responsible for transmission of chicken sarcoma
1970 Bishop & Varmus showed that mammalian cells have a
src gene
How did RSV get a src gene?
Retroviruses copy their RNA genome into DNA using reverse
transcriptase
RSV genome integrates into host genome randomly
At some point, an RSV genome lands next to the host src gene
When the region is transcribed, the src open reading frame is
accidently copied into the RSV genome

Discovering oncogenes

Extract DNA from a tumor

Transfect it into cells in culture in a petri dish
Normal cells grow as a monolayer
Identify clumps of cells (foci) that can pile up on
each other
Grow them up, characterize DNA that has been
taken up to identify the oncogene

Proto-oncogenes:
typically encode
growth factors,
growth factor
receptors, GTPbinding proteins, &
transcription factors

Finding tumor suppressors: more difficult,

often discovered as familial pre-disposition
genes. Like Retinoblastoma gene (Rb)

How Rb controls the G1-to-S transition

P53: a
major
tumor
suppressor

26

Proto-oncogenes often encode

component of signal transduction
pathways
Signal-transduction pathways
External signal triggers a cascade of
intracellular reactions producing a specific
response
Ras protein

Transmembrane receptors:
Overrepexpression may
allow signaling without
growth factor binding
Mutation can make
tyrosine kinase
constitutively active
Ras: mutated in 20-30%
of all cancers
Activating mutations
leave Ras in on (GTPbound) state

Alterations in cell physiology that

underlie malignant growth

BLC2 and the importance of death

Follicular B-cell lymphoma

Fairly indolent disease
Translocation between Chr 18 and Chr 14
Bcl2 gene comes under the control of an
Immunoglobulin gene enhancer
Get overproduction of Bcl2 protein

Alterations in cell physiology that

underlie malignant growth: angiogenesis

Angiogenesis

Angiogenesis in an
experimental model of
subcutaneous cancer
xenograft

Genentech angiogenesis cartoon

Angiogenesis Factors
Vascular endothelial cell growth factor
Fibroblast growth factor
Matrix metalloproteinases

Slide from Ed Gabrielson

The Immune System and Cancer

Inflammation increases risk of carcinogenesis

Hepatitis and hepatocellular carcinoma
Helicobacter pylori and gastric cancer

Anti-cancer immune response

Cytotoxic and memory T-cells

Slide from Ed Gabrielson

How Cancers are Treated

Localized Disease
Surgery
Radiation
Medical therapies
Traditional cytotoxic chemotherapies
Targeted therapies

Combinations

Metastatic
Surgery at times
Radiation often
Medical therapies
Immunotherapies

DNA-damaging chemotherapies
often increase risk for other cancers
to develop later

Why We're Losing The War On Cancer

[And How To Win It] (FORTUNE
Magazine, 2004)
Clifton Leaf & Doris Burke

Robert Weinberg: "A fundamental problem which

remains to be solved in the whole cancer research
effort, in terms of therapies, is that the preclinical
models of human cancer, in large part, stink."

Mouse models of cancer: xenografts

HUMAN TUMOR CELLS

"99% of investigators in industry and in academia use xenografts."

Why? "It is very convenient, easily manipulated "You can assess
tumor size just by looking at it." V. Dixit, VP for Research in
molecular oncology, Genentech, quoted in Fortune.

Shortfalls of xenografts
Xenograft shrinkage is poor predictor of efficacy in
humans
Cannot accurately replicate tumor microenvironment
Metastasis is exceedingly rare

What are the

alternatives?

Genetically engineered mouse (GEM) models

Technologies to add or subtract genes from mice
Cancer molecular genetics and genome sequencing
Make cognate mutations in mice

Does it
work?
Rarely
.
Why not?

Why is it hard to make good GEM models of

prostate cancer ?

Mouse
geneticists, selftrained in
rodent
pathology

Human
pathologists, no
formal training
in rodent
pathology

k of essential genetic tools: tissue-specific regulatory elemen

A different approach
Develop the necessary genetic tools
Bring in human prostate pathology expertise
Model central oncogenic & tumor suppressor
pathways most often altered in human prostate
cancer
Mouse
geneticists,
self-trained
in rodent
prostate
pathology

Human
pathologists
, no formal
training in
rodent
prostate
pathology

Angelo De Marzo, MD, PhD

Hoxb13/MYC

Fl/Fl
Hoxb13-Cre/Pten
Hoxb13/Cre|

PtenFl/FL

Hoxb13-MYC/ Hoxb13-Cre/PtenFL
Hoxb13/MYC|Hoxb13/Cre|
PtenFl/FL

FVB

Hoxb13/MYC|
Hoxb13/Cre|PtenFl/FL

CK18

Poorly differentiated prostate adenocarcinoma