Lynch Syndrome

Overview

Lynch Syndrome is the most common cause of hereditary colorectal cancer. It is the
result of an autosomal dominant mutation in DNA mismatch repair genes. Individuals
with the syndrome are often asymptomatic until they present with advanced colorectal
cancer due to the rapid progression of a small number of adenomas to malignant
tumors. There is an additional increased risk of other cancers as well such as
endometrial, ovarian, and gastric cancer. Some patients develop urothelial, skin, small
bowel, brain, or biliary tract cancer as well.

Epidemiology

- Most common inherited cause of colorectal cancer

o 3-8% of new colorectal cancers are attributable to Lynch syndrome
- Approximately 70-80% lifetime risk of developing Lynch syndrome associated
cancer, but sources vary on this statistic
o There is a lifetime risk for Colorectal cancer anywhere from 10-47%
depending on the mutation inherited
- Different gene mutations are associated with greater or lesser risks for different
other cancers in addition to colorectal cancer

- Mutations in MLH1 and MSH2 are reported in 60-80% of Lynch syndrome

cancers
o MSH6 mutation is the third most common and PMS2/EpCAM mutations
are very rare
 - Affected individuals develop colorectal cancer much earlier (45-60y/o) than
sporadic cases (~69y/o)
Pathophysiology

- The development of cancer in Lynch syndrome occurs via the microsatellite

instability pathway
- Inheritance of a mutation in a DNA mismatch repair gene (MMR) leads to the
syndrome (autosomal dominant inheritance)
o Five MMR genes are associated with Lynch syndrome
 MLH1
 MSH2
 MSH6
 PMS2
 EPCAM (this gene is upstream of MSH2 and affects its
transcription via epigenetic silencing)
- When a second hit to the affected gene occurs, the affected cell loses its ability
to repair mismatched nucleotides leading to the rapid accumulation of mutations
o This is called microsatellite instability (MSI)
 The normal genome contains two nucleotide repeated sequences
(microsatellites)
 These sequences are a different molecular weight than the rest of
the genome and so the microsatellites separate out in
electrophoresis
 When MMR genes are lost in tumor cells, these microsatellites start
to grow in size and become “unstable”  this is a sign that a
mutation in MMR has occurred
o Rapidly accumulating mutations in tumor cell DNA can lead to the
acquisition of several other driver mutations that lead to malignancy
o TGF-beta receptor often becomes mutated
 It is normally responsible for the inhibition of cellular proliferation
 Mutation causes unregulated growth
o BAX can acquire a mutation
 BAX is a pro-apoptotic protein that facilitates the intrinsic pathway
of apoptosis
 When mutated, tumor cell becomes resistant to apoptosis
o BRAF acquires a mutation
 This is a proto-oncogene that can acquire a gain of function
mutation resulting in tumor genesis

The MMR genes code for proteins that complex together into heterodimers. Some
combinations of these heterodimers are responsible for identifying DNA mismatch
errors and others are responsible for repairing the error.

- MutS-alpha/MutS-beta recognize DNA mismatch errors

- MutL-alpha/MutL-beta/MutL-gamma repair the error
Losing both alleles of any one of the MMR genes results in a breakdown of the entire
system.

- MSI can result from a second hit after an inherited MMR gene mutation
- Sporadic colorectal cancers that follow the MSI pathway occur when there is
somatic hypermethylation of MMR genes
o These tumors are sometimes called CIMP+ tumors (for CpG Island
Methylator Phenotype)
o This usually results in a sessile serrated adenoma that progresses to
carcinoma

- Pts develop right sided mucinous adenocarcinoma of the colon

o The preceding adenomas are usually flat and large with a high grade of
dysplasia
o Signet cells are sometimes observed (cells with large vacuoles)
o Lymphocytic infiltration is seen due to the expression of neoproteins by
the tumor cells
o

Clinical Features

- Patients are usually asymptomatic until they present with abdominal pain or
blood in the stool
- Lynch-associated adenomas are usually flat and large
o They progress to carcinomas very rapidly
o 35months compared to 10-15 years for the normal adenoma-carcinoma
sequence
o They are usually highly dysplastic
o Signet ring cells can be seen
 Cells with large cytoplasmic vacuoles commonly seen in
adenocarcinoma
o Lymphocytic infiltration can be seen as well
 Sometimes described as Crohn’s-like
- Average age of presentation is 44 years old
- Patient will be asymptomatic, then develop symptoms of right sided colon cancer;
there will also be a history of lynch syndrome associated cancer in first degree
relatives
- Subtypes include Muir-Torre and Turcot
o LS + skin tumors (sebaceous adenoma/keratoacanthoma) = Muir-Torre
 Especially associated with MSH2 mutation
o LS + glioma (B&B says medulloblastoma) = Turcot

Management
 - First degree relatives should undergo genetic screening
- Screening for different cancers should begin earlier in life than normal
o Annual/biennial colonoscopy starting at 20-25
o Annual pelvic ultrasound with endometrial biopsy (female) starting at 30
o Annual upper endoscopy starting at 30
- Patients who develop colon cancer should have a colectomy with ileorectal
anastomosis
o Because of the high rate of recurrence or development of new cancer in
the colon, total colectomy is usually preferred
o Elderly patients may benefit from undergoing only hemicolectomy
- For metastatic CRC from LS, immune checkpoint inhibitors are used
o Pembrolizumab
o Nivolimab/Ipilimumab

Resources

Bonadona V. Cancer Risks Associated With Germline Mutations in MLH1, MSH2,

and MSH6Genes in Lynch Syndrome. JAMA. 2011; 305(22): 2304-2310.

Sinicrope F. Lynch Syndrome–Associated Colorectal Cancer. N Engl J Med. 2018; 379:

764-773.

Giardiello FM. Guidelines on Genetic Evaluation and Management of Lynch Syndrome:

A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am
J Gastroenterol. 2014; 109(8): 1159-1179.

Molecular Genetics of Colon Cancer. UpToDate.

B&B. Colon Cancer

Robbins. Ch 14

AMBOSS. Lynch Syndrome