661

CDK-220/ vol. 41 no. 9, th. 2014

TINJAUAN PUSTAKA
INTRODUCTION
Colorectal cancer (CRC) is one of three most
common cancer in Indonesia with incidence
rate of 19.1 for men and 15.6 for women
per 100.000 population
1
and also important
cause of morbidity and mortality among non-
infectious diseases in developing country.
2

Environmental factor is a dominant cause of
CRC, however, inherited genetic factor is also
signifcant in between 15% and 30% of cases,
more than 5% of all CRC cases are associated
with a highly penetrant dominant or recessive
inherited syndrome. The most common form
of colorecatal hereditary cancer syndrome is
Lynch Syndrome accounted for 2% to 4% of
all CRC cases.
3,4
Predisposed individual from
Lynch syndrome family have approximately
60 to 80% life-time risk for developing CRC.
5
The most important step leading to the
diagnosis of a hereditary cancer syndrome is
collection of thorough family history of cancer,
it is the most cost-efective method to identify
hereditary cancer syndrome.
11
The focus
should be on identifying cancer, the family
members age at the frst diagnosis/onset
of cancer, any pattern of multiple primary
cancers, any association with phenotypic
features that may be related to cancer, such
as colonic adenomas; and documentation
of pathological fndings whenever possible.
These information will frequently help to
identify a hereditary cancer syndrome in the
family.
5
The risk associated with a family history of
CRC depends on the number of afected
relatives and the age at frst diagnosis.
People with one family degree relatives
(FDR) with CRC diagnosed at age >50
years have a relative risk (RR) of 2 to 3 for
developing CRC, while subjects with two (or
more) FDR with CRC diagnosed at any age,
or with one FDR with CRC diagnosed before
the age of 50 years have a relative risk of 4
to 6 for developing CRC.
6
After complete
family history, molecular genetic testing may
then provide verifcation of Lynch Syndrome
diagnosis, whether a germ-line mutation is
present in the family.
7
ETIOLOGY
Lynch syndrome has been known historically
as hereditary nonpolyposis colorectal cancer
(HNPCC). It is characterized by an increased
risk of colon cancer and other related cancer
such as cancers of the endometrium, ovary,
stomach, small intestine, hepatobiliary tract,
urinary tract, brain, and skin.
8
The life time risks
for cancer in subject with Lynch syndrome
are: 52%-82% for colorectal cancer (mean
age at diagnosis 44-61 years), 25%-60% for
endometrial cancer in women (mean age at
diagnosis 48-62 years), 6% to 13% for gastric
cancer (mean age at diagnosis 56 years),
and 4%-12% for ovarian cancer (mean age
ABSTRACT
Colorectal cancer (CRC) is one of three most common cancer in Indonesia. More than 5% CRC cases are associated with inherited gene
mutation called Lynch Syndrome. Lynch syndrome is caused by a germline mutation in a mismatch repair gene (MMR) gene (MLH1, MSH2,
MSH6, and PMS2). Individual with these gene mutation have approximately 60 to 80% life-time risk for developing CRC. Lynch syndrome is
also related to increased risk of other cancers such as cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary
tract, brain, and skin. Lynch syndrome is diagnosed based on family history according to criteria of National NCCN, immunohistochemistry and
genetic testing. Identifcation of people who are predisposed to hereditary colorectal cancer is very important, to allow clinicians assess the
efective prevention, early detection and intervention to decrease morbidity and mortality.
Key words: Lynch syndrome, colorectal cancer, inherited gene mutation
ABSTRAK
Kanker kolorektal (KKR) merupakan satu dari tiga kanker terbanyak di Indonesia. Lebih dari 5% kasus KKR berkaitan dengan mutasi gen yang
diturunkan yang disebut sebagai sindrom Lynch. Sindrom Lynch disebabkan oleh mutasi germline pada gen mismatch repair (MMR) yang
meliputi MLH1, MSH2, MSH6, dan PMS2. Individu dengan mutasi gen tersebut memiliki 60-80% life-time risk untuk KKR. Sindrom Lynch juga
berhubungan dengan peningkatan risiko kanker lain seperti kanker endometrium, ovarium, gaster, usus halus, traktus hepatobilier, traktus
urinarius, otal dan kulit. Sindrom Lynch didiagnosis berdasarkan data riwayat keluarga sesuai kriteria NCCN, pemeriksaan imunohistokimia
dan pemeriksaan genetika. Indentifkasi individu pengidap sindrom Lynch sangat penting untuk pencegahan, skrining, dan intervensi dini,
dan untuk menurunkan angka mortalitas dan morbiditas. Catharina Endah Wulandari. Lynch Syndrome.
Kata kunci: Sindrom Lynch, kanker kolorektal, mutasi gen yang diturunkan
Alamat korespondensi email: catharinaawalliya@gmail.com
Lynch Syndrome
Catharina Endah Wulandari
Pusat Riset Biomedis (Centre of Biomedical Research/CEBIOR),
Fakultas Kedokteran Universitas Diponegoro, Semarang, Indonesia
CDK-220/ vol. 41 no. 9 th. 2014
662
TINJAUAN PUSTAKA
family with a germline mutation in one of
four mismatch repair (MMR) genes (MLH1,
MSH2, MSH6, and PMS2) or in EPCAM.
Minimum criteria for clinical defnition of
Lynch syndrome are listed below (Amsterdam
I Criteria)
12
:
At least three relatives with colorectal cancer
(CRC); all of the following criteria should be
present:
1. One should be a frst-degree relative of
the other two
2. At least two successive generations must
be afected
3. At least one of the relatives with
colorectal cancer must have received the
diagnosis before age of 50 years
4. Familial adenomatous polyposis (FAP)
should be excluded
5. Tumors should be verifed by pathologic
examination.
Revised minimum criteria for clinical defnition
of HNPCC (Amsterdam II Criteria)
9
:
At least three relatives must have a cancer
associated with hereditary nonpolyposis
colorectal cancer (colorectal, cancer of
endometrium, small bowel, ureter or renal
pelvis); all of the following criteria should be
present:
1. One must be a frst-degree relative of the
other two
2. At least two successive generations must
be afected
3. At least one of the relatives with cancer
associated with hereditary non-polyposis
colorectal cancer should be diagnosed before
age of 50 years
4. Familial adenomatous polyposis (FAP)
should be excluded in the colorectal cancer
case(s) (if any)
5. Tumors should be verifed whenever
possible.
Revised Bethesda Guidelines for heredi-
tary non-polyposis colorectal cancer/Lynch
Syndrome and Microsatellite instability
1
:
1. Colorectal cancer diagnosed in a patient
who is less than 50 years of age
2. Presence of synchronous or metachro-
nous Lynch-syndrome associated tumor,
regardless of age
3. Colorectal cancer with the MSI-H histo-
logy diagnosed in a patient who is less than
60 years of age
4. Colorectal cancer diagnosed in patient
with one or more frst-degree relatives with
an LS-related cancer with one of the cancer
being diagnosed under age 50 years
5. Colorectal cancer diagnosed in a patient
with two or more frst- or second-degree
relatives with LS-related cancer regardless of
age.
For this guideline, Lynch syndrome-related
tumors included colorectal, endometrial,
gastric, ovarian, pancreas, ureter, renal pelvis,
biliary tract, small bowel carcinoma, brain and
sebaceous skin tumors.
Patients meeting the revised Amsterdam II
and Bethesda Guidelines should be ofered
to undergo tumor testing for microsatellite
instability (MSI) and/or Immunohisto-
chemistry (IHC) analysis of tumour. A high
level of MSI (two or more microsatellite
markers show tumour instability), or loss of
expression of a DNA mismatch repair protein
by IHC, comprise tumor phenotypes that
indicate defective DNA mismatch repair. This
fnding can be found in 90% colon cancers
associated with Lynch syndrome, whereas
in sporadic CRC it is found in about 15% of
cases.
3
Diagnosis testing
Revised Amsterdam II and Bethesda guide-
lines are appropriate tools to help in selecting
families for molecular genetic testing and/or
IHC analysis of tumours to establish diagnosis
of Lynch Syndrome.
Patient meeting these criterias should be
ofered to undergo these following tests:
1. Immunohistochemistry (IHC)
Immunohistochemistry (IHC) detect the
at diagnosis 42.5 years, approximately 30%
are diagnosed before age 40 years). The risk
for other Lynch syndrome-related cancers is
lower, although the persentage is higher than
in general population.
6,9
Lynch syndrome is caused by a germline
mutation in a mismatch repair gene (MMR)
gene (MLH1, MSH2, MSH6, and PMS2)
and associated with tumors exhibiting
microsatellite instability (MSI). Microsatellite
is repetitive sequence of exist DNA. There
is increase variability in the length of the
sequences in tumors due to Lynch syndrome,
called instability (Figure 1).
10
The four mismatch repair (MMR) genes are
inherited by autosomal dominant pattern.
These genes are normally responsible for
correcting mistakes in genetic code, which
is made of DNA. Because cells grow and
divide, they make copies of their DNA and
sometimes some minor mistakes occur.
Normal cells have mechanisms to recognize
and repair mistakes. But individuals who
inherit one of the abnormal genes associated
with Lynch syndrome lack the ability to
repair these minor mistakes; accumulation
of these mistakes leads to increasing genetic
damage within cells and eventually can lead
to becoming cancerous cells.
11
DIAGNOSIS
According to the Guideline from National
Comprehensive Cancer Network (NCCN),
Lynch syndrome diagnosis can be establish-
ed based on family history meeting Bethesda
or Amsterdam criteria who have tumor
microsatellite instability (MSI) or on the basis
molecular genetic testing in an individual or
Figure 1 Microsatellite instability
Microsatellite Replication
Adapted from Gruber SB, Kohlmann W. The genetics of hereditary nonpolyposis colorectal cancer. J Nat Comp
Cancer Net. 2003;1:137-44.
Normal Abnormal (Mismatch repair defect)
663
CDK-220/ vol. 41 no. 9, th. 2014
TINJAUAN PUSTAKA
presence or absence of protein products
expressed by mismatch repair genes. IHC for
loss of MMR gene products (MLH1, MSH2,
MSH6, PMS2) has 92% sensitivity for Lynch
syndrome related to germline mutation, and
can help pinpoint which gene to target for
mutation analysis.
a. A germline mutation in MLH1 results in
loss of expression of protein MLH1/PMS2,
b. A germline mutation in MSH2 result in
loss of expression of protein MSH2/MSH6,
however,
c. A germline mutation in MSH6 and PMS2
typically do not result in loss of MSH2 or
MLH1 expression due to the fact that these
proteins are still present in other pairings.
2
IHC and related gene mutation are
summarized in Table 1.
Table 1 Expression of protein in IHC testing related to gene
mutation
Immunohistochemistry
Mutation
MLH1 MSH2 MSH6 PMS2
- + + - MLH1
+ - - + MSH2
+ + - + MSH6
+ + + - PMS2
2. Microsatellite instability (MSI) testing of
tumor tissue
Genes in the mismatch repair (MMR) path-
way play an important role for identifying
and repairing single nucleotide mismatches
and insertion or deletion loops that occur
when cells grow and divide. Defects in the
genes involved with mismatch repair cause
an accumulation of somatic mutations in a
cell, which may result in the cell developing
malignant.
Microsatellites are part of DNA with a
repetitive sequence of nucleotides (e.g.,
AAAAA or CGCGCGCG) that are susceptible
to errors when mismatch repair gene function
is impaired. Cancers presenting in cells with
defective mismatch repair gene function
show an inconsistent number of micro-
satellite nucleotide repeats when compared
to normal tissue, this fnding called as
microsatellite instability.
8
MSI, tested using panel of microsatellite
markers, is compared in tumor tissue

and normal tissue. Five markers (BAT25,
BAT26, D2S123, D5S346, and D17S250) are
recommended by a 1997 NCI consensus.
3
A
tumor is classifed as listed below:
a. MSI-high if more than two (or >30%) of
the markers show instability
b. MSI-low if one (or <30%) of the markers
show instability
c. MSI-stable if 0 (or 0%) of the markers
show instability
3. Mutation analysis
Genes in the mismatch repair (MMR) path way
(MLH1, MSH2, MSH6, PMS2) in which germ-
line mutation could happen, cause Lynch
syndrome. Currently, EPCAM gene has been
found to be the cause of Lynch syndrome.
Although EPCAM is not a MMR gene,
Table 2 Summary of Germline Molecular Genetic Testing Used in Lynch Syndrome
Gene
Proportion of Lynch
Syndrome attributed in
this gene
Test method Mutation detected
MLH1 50%
Sequence analysis Sequence variant
Duplication/deletion analysis Exonic or whole-gene deletion
MSH2 40%
Sequence analysis Sequence variant
Duplication/deletion analysis Exonic or whole-gene deletion
MSH6 7-10%
Sequence analysis Sequence variant
Duplication/deletion analysis Exonic or whole-gene deletion
PMS2 5%
Sequence analysis Sequence variant
Duplication/deletion analysis Exonic or whole-gene deletion
EPCAM
(TACSTD1)
~1-3% Duplication/deletion analysis Exonic or whole-gene deletion
Abnormal expression
or
MSI-H/L
Abnormal
expression
Normal
expression
Normal expression
or MSS
MSI-L/H
MSI
MSS
IHC IHC or MSI
Suspected Lynch
Syndrome
(Revised Bethesda
Criterias)
High probability of
carrying a mutation
Low probability of
carrying a mutation
Mutation analysis Possible phenocopy
analysis second
tumour
Mutation
analysis
No mutation
analysis
Figure 2 Strategy for identifcation of patients with colorectal cancer with a mismatch repair gene defect
2
IHS, immunohistochemical; MSI, microsatellite instability; MSS, microsatellite stability
CDK-220/ vol. 41 no. 9 th. 2014
664
TINJAUAN PUSTAKA
recurrent germline deletions of the 3 region
results in silencing the adjacent downstream
MSH2 by hypermethylation.
4-5
This following chart summarize steps for
Lynch syndrome diagnosis (Figure 2):
MANAGEMENT
In general, management of Lynch Syndrome
can be divided into two goals; frst,
management of colon cancer in a person
with Lynch Syndrome, and the second,
cancer risk management for related family in
which Lynch syndrome diagnosis established
(primary prevention).
1. Management of Colorectal Cancer
The main treatment for colorectal cancer
related to Lynch syndrome is surgical. Several
studies have shown that Lynch syndrome
patients have an increased risk of developing
multiple (synchronous and metachronous)
CRCs, therefore, if colon cancer detected,
more extensive treatment (total or subtotal
colectomy) with ileorectal anastomosis is
recommended rather than a segmental
or partial colonic resection.
4,8
In a study, a
decision analysis was performed to compare
the life expectancy for patients undergoing
subtotal colectomy or partial colectomy
for a primary CRC. The results showed that
subtotal colectomy performed at a young
age (47 years) would lead to an increased
life expectancy of up to 2.3 years.
6
Though
this result suggest that extensive surgical
treat ment is efective in Lynch syndrome, it is
important to consider the risk of developing
a second cancer under appropriate (post-
operative) surveillance and the efect of more
extensive surgery on functional outcome
and quality of life, to determine beneft to
patient.
7
2. Cancer risk management
a. Surveillance for Colorectal Cancer
NCCN guideline recommend colonoscopy
and removal of polyps (if positive) beginning
at age 20-25 years or 10 years before the
earliest age of CRC diagnosis in the family,
and repeat every 1-2 years.
8
Several study
showed that periodic examination by
colonoscopy could detect CRC at an earlier
stage, and reduce up to 63% risk of CRC and
signifcantly reduce the mortality associated
with CRC.
4,9
Periodic removal of polyps
reduces the incidence of CRC in individuals
with Lynch syndrome.
11
Prophylactic surgery is not routinely
recommended for individuals at risk of CRC
because colonoscopy is efective. Subtotal
colectomy with ileorectal anastamosis has
been advised by some experts if a colon
cancer is detected because of the very high
rate of metachronous CRC (up to 30%).
11
b. Surveillance for Extra-Colonic Cancer
Extra-colonic cancer related to Lynch
Syndrome includes endometrial cancer and
ovarian cancer as the most common cancer,
followed by gastric cancer and duodenal
cancer, urinary tract cancer, pancreas,
hepatobiliary tract and brain cancer with
lower incidence.
8
Endometrial and ovarian
cancer surveillance could include annual
transvaginal ultrasound, pelvic examination,
annual Pap smear, and/or endometrial biopsy
and CA-125 blood test beginning at 25-30
years of age.
4,11,21
Upper gastrointestinal endoscopy could
be used to screen for gastric and duodenal
cancer. Annual screening urinalysis and
cytology to detect cancer of renal pelvis is
generally advised because inexpensive and
noninvasive, although evidence of ef cacy is
Continued screening
Consider prophylactic total
abdominal hysterectomy with
bilateral salpingo-oophorectomy
(TAH/BSO) if postmenopausal
or family completed
Endocopic polypectomy with
follow-up colonoscopy every 1-2 y
depending on:
Location, character
Surgical risk
Patient preference
Total abdominal colectomy with
ileorectal anastomosis
Consider TAH/BSO at time of
colon surgery if postmenopausal
or family completed
Treatment for
adenocarcinomas
FOLLOW-UP
Colon cancer:
Colonoscopy at age 20-25 y or 10 y prior to the youngest
age at diagnosis in the family, whichever comes first and
repeat every 1-2 y.
Extracolonic:
Endometrial and ovarian cancer
Consider referral to gynecologic oncologist for
screening for gynecologic tumors
Encourage patient education and prompt response to
endometrial cancer symptoms
Prophylactic hysterectomy and bilateral
salpingoophorectomy is a risk reducing option for
women who have completed childbearing.
Gastric and duodenal cancer: consider upper GI endoscopy
(including side-viewing examination) at age 25-30 y and
repeat every 1-3 y depending on findings.
Urothelial cancer: consider annual urinalysis
CNS cancer: Annual physical examination; no additional
screening recommendation have been made.
Pancreatic cancer: No recommendation have been made.
No pathologic
finding
Adenocarcinomas
Adenoma
Adenomas not
amenable to
endoscopic
resection or high-
grade dysplasia
SURVEILLANCE
Endoscopic
rectal exam
every 1-2 y
Figure 3 Management of cancer risk in Lynch Syndrome
21
665
CDK-220/ vol. 41 no. 9, th. 2014
TINJAUAN PUSTAKA
lacking.
11,21
No specifc screening for cancers
of the pancreas, hepatobiliary tract, or brain is
recommended.
21
Management for cancer risk are summarized
by following chart (Figure 3):
SUMMARY
Colorectal cancer (CRC) is one of three most
common cancer in Indonesia with incidence
rate of 19.1 for men and 15.6 for women per
100.000 population
13
and also important
cause of morbidity and mortality among
non-infectious diseases in developing
country.
14
The most common form of
colorecatal hereditary cancer syndrome is
Lynch Syndrome accounted for 2% to 4% of
all CRC cases.
15,16
Revised Amsterdam II and
Bethesda guidelines are appropriate tools
to help in selecting families for molecular
genetic testing and/or IHC analysis of
tumours to establish diagnosis of Lynch
Syndrome. Management of Lynch Syndrome
can be divided to: frst, management of colon
cancer in a person with Lynch Syndrome, and
second, cancer risk management for related
family (primary prevention).
REFERENCES
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; in press
2. Oemiati R, Rahajeng E, Kristanto A. Prevalensi Tumor dan Beberapa Faktor yang Mempengaruhinya di Indonesia. Bul. Penelit. Kes. 2011; 39:190-204.
3. Kastrinos F, Syngal S. Screening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For? J. Clin. Oncol.
4. Vasen H, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer. J Med Genet 2007;44:353-
62.
5. Jong A, Vasen H. The frequency of a positive family history for colorectal cancer: a population-based study in the Netherlands. J Med 2006;64(10).
6. St John DJ, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993;118:785-90.
7. Lynch H, Chapelle A. Hereditary Colorectal Cancer.N Engl J Med 2003;348:919-32.
8. Kohlmann W, Gruber S, Arbor A. Lynch Syndrome. [serial online] updated 2012 Sept 20 [cited 2013 Nov 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211
9. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer. 1999;81(2):214-8.
10. Gruber SB, Kohlmann W. The genetics of hereditary non-polyposis colorectal cancer. J Natl Compr Canc Netw. 2003;1:137-44.
11. Lindor NM, et al. Concise handbook of familial cancer susceptibility syndromes. Journal of the National Cancer Institute Monographs. 2008;38:1
12. Vasen HFA. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Onc 2000;18 (suppl 1):81s-92s.
13. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst
2004;96(4)261-8.
14. Bellizzi AM, Frankel WL. Colorectal cancer due to defciency in DNA mismatch repair function: a review. Adv Anat Pathol. 2009;16:405-17.
15. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial
predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998 Nov 15;58(22):5248-57.
16. Niessen RC, Hofstra RM, Westers H, Ligtenberg MJ, Kooi K, Jager PO, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes
Chromosomes Cancer. 2009;48:737-44.
17. Goel A, Nguyen TP, Leung HC, Nagasaka T, Rhees J, et al. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with
derivation of the epimutation on the paternal allele in one. Int J Cancer. 2011;128:869-78.
18. Kuiper RP, Vissers LE, Venkatachalam R, Bodmer D, Hoenselaar E, Goossens M, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32:407-
14.
19. De Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, Cats A, Menko FH, Grif oen G, Slors JF, Nagengast FM, Kleibeuker JH, Vasen HF. Decision analysis in the surgical treatment
of colorectal cancer due to a mismatch repair gene defect. Gut 2003;52:1752-5.
20. Vasen HF, Blanco I, Collan KA, Gopie J, Alonso A, Aretz S, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European
experts. Gut 2013;62:812-823
21. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Colorectal Cancer Screening. Updated 2010 [cited 2013, July 17]. Available from: www.nccn.
org.
22. Arrigoni A, Sprujevnik T, Alvisi V, Rossi A, Ricci G, et al. Clinical identifcation and long-term surveillance of 22 hereditary non-polyposis colon cancer Italian families. Eur J Gastroenterol
Hepatol 2005;17:213-19.
23. Renkonen-Sinisalo L, Sipponen P, Aarnio M, et al. No support for endoscopic cancer risk management for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol.
2002;37:574-7.