Lynch Syndrome

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Syndrome

Epidemiology and Etiology:

· Autosomal dominant

· Incomplete penetrance

· De novo mutation in an MMR gene is thought to be rare (Bisgaard & Bernstein 2003)

· 2-4% of CRC patients

· 2.5% of Endometrial cancer patients

· Lynch syndrome I:

· Colon manifestations only

· Lynch syndrome II:

· Extracolonic manifestations present

Common sites:

· Colon

· Polyps (low numbers)

· Flat adenomas

· Adenocarcinoma (52-82% lifetime risk)

· Lynch syndrome accounts for approximately 1-3% of colon cancers

· 44-61 years average age

· Mucinous

· Signet ring

· Prominent tumour infiltrating lymphocytes

· No preexisting adenoma usually

· Duodenum & jejunum

· adenocarcinoma

· Stomach

· Adenocarcinoma, intestinal type (6-13% lifetime risk)

· Mean age 56 years

· Uterus

· Endometrial carcinoma (20-60 % risk in women)

· 46-62 years average age

· Ovary

· Carcinomas (4-12% risk)

· Histologic types similar to sporadic distribution

· Not borderline tumours

· Mean age 42.5 years

· Liver

· Cholangiocarcinoma

· Pancreas

· Carcinoma

· Upper urinary tract

· Transitional cell carcinomas of pelvis and ureter

· Skin

· Sebaceous skin tumours (Muir-Torre)

· Brain

· Glioblastoma (Turcot syndrome)

Gross features:

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Histologic features:

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Immunophenotype:

Marker:	Sensitivity:	Specificity:
MSH2 (neg)
MLH1 (neg)
MSH6 (neg)

Molecular features:

· See MMR / MSI testing guidelines notes

· Mutations in DNA repair genes leading to microsatellite instability

· MSH2 (60%)

· 20% of these are large deletions or rearrangements

· MSH2 protein can pair with MSH6 or MSH3 proteins

· MLH1 (30%)

· MLH1 protein can pair with PMS2 or PMS1 proteins

· MSH6 (7-10%)

· PMS2

· EPCAM (1%)

· Results in loss of expression of MSH2 due to its close proximity

· Few case reports of uncertain significance also detected in:

· PMS1

· TFGBR2

· MLH3

· MMR IHC (92% sensitivity for individuals with Lynch – Shia 2008) (range of 74-100% - CCO evidence review)

· 4 proteins:

· MLH1

· PMS2

· MSH2

· MSH6

· Loss of expression may be due to mutation, or instability due to mutation in its obligate partner

· MLH1 methylation analysis:

· of tumour tissue

· majority of MSI is caused by somatic methylation of the promoter region of MLH1

· MLH1 promoter methylation can help eliminate the diagnosis of Lynch

· However, it can occur as a “second hit” in an individual with Lynch

· BRAF mutation (15% of colorectal cancers)

· Most common is NM_004333.4:c.1799T>A (p.Val600Glu, or V600E)

· Rare in Lynch syndrome-related cancers

· Not helpful in Endometrial cancers due to low incidence

· MSH2/MLH1 sequencing or mutation scanning

· Wont detect large deletions / rearrangements

· MLPA or qPCR or SB for large deletions

Other features:

· Amsterdam Criteria:

· Three affected relatives with any combination of colorectal, endometrial, small bowel, ureter, transitional cell kidney cancer (urothelial), sebaceous adenoma/carcinoma and/or keratoacanthoma.

· One should be a first-degree relative of the other two.

· At least two successive generations should be affected.

· At least one diagnosis must be before age 50 years.

· Tumour type should be confirmed by review of pathology or other medical records.

· Bethesda Guidelines:

· age < 50 y

· presence of synchronous, metachronous colorectal CA

· presence of other HNPCC-associated tumours

· MSI-H histology (see above) in a patient younger than 60 y

· Colorectal CA in 1 or more 1^st degree relatives with an HNPCC related tumour, one of the CA’s being diagnosed at < 50 y

· Colorectal CA in 2 or more 1^st degree relatives with an HNPCC-related tumour, regardless of age

· Approximately 25% of individuals with germline pathogenic variant in an MMR gene did not meet Amsterdam or Bethesda guidelines

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004.

· OMIM

· Genetests.org

· GeneReviews (May 2014)

· Genetics Home Reference (May 2013)

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