Lynch syndrome

Last author update: 29 January 2021
Last staff update: 3 May 2022

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PubMed Search: Lynch syndrome [title] colon

Jennifer Findeis-Hosey, M.D.
Raul S. Gonzalez, M.D.
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Cite this page: Findeis-Hosey J, Gonzalez RS. Lynch syndrome. website. Accessed May 19th, 2024.
Definition / general
  • Autosomal dominant hereditary disorder due to mutation in a mismatch repair (MMR) gene
Essential features
  • Most common hereditary colorectal carcinoma syndrome (accounts for 2 - 5% of all colorectal carcinomas)
  • 80% of patients develop colorectal carcinoma; also increased risk of endometrial carcinoma (33%), ovarian carcinoma (5%) and cancers of small bowel, stomach, upper urinary tract and brain (Fam Cancer 2005;4:245)
  • Muir-Torre syndrome is a clinical variant
  • See also MSI testing for Lynch syndrome, MLH1, MSH2
  • Patients with Lynch syndrome tend to develop carcinomas at an earlier age than the general population (average age: 44 years old)
  • Colon cancers more likely to occur in the proximal colon
Pathophysiology / etiology
  • Mutation in MMR gene results in defective repair of DNA sequence mismatches, which most frequently occur in long, repetitive DNA sequences (such as seen in microsatellite regions, hence the term microsatellite instability [MSI])
  • Accumulation of DNA mismatches lead to increased risk of developing malignant neoplasms
  • Typically due to mutation in an MMR gene: most commonly due to a germline mutation in MSH2 or MLH1; less frequently due to germline mutations in MSH6 or PMS2
  • Mutations in EPCAM (epithelial cellular adhesion molecule) / TACSTD1 (tumor associated calcium signal transducer 1) gene may result in Lynch syndrome: EPCAM gene is adjacent to MSH2 and mutations in EPCAM may result in MSH2 promoter hypermethylation and subsequent inactivation of MSH2
  • Rarely due to inactivation through germline promoter hypermethylation of MLH1; differs from the somatic MLH1 hypermethylation, which may be seen in sporadic colon cancers
  • Rarely the result of inactivation of CHEK2 (cell cycle checkpoint kinase 2)
  • Amsterdam I screening criteria (all 4 must be met):
    • 3 or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
    • 2 successive affected generations
    • 1 or more colon cancers diagnosed before age 50
    • Familial adenomatous polyposis has been excluded (Dis Colon Rectum 1991;34:424)
    • These criteria are relatively sensitive but not specific for Lynch syndrome, since these patients may lack MMR gene mutations
  • Amsterdam II criteria (all 4 must be met):
    • 3 or more family members with HNPCC related cancers, one of whom is a first degree relative of the other two
    • 2 successive affected generations
    • 1 or more HNPCC related cancers diagnosed before age 50
    • Familial adenomatous polyposis has been excluded (Gastroenterology 1999;116:1453)
  • Revised Bethesda criteria (any criteria must be met; these are guidelines for when tumors should be tested for MSI):
    • Colorectal cancer diagnosed before age 50 years
    • Presence of synchronous or metachronous colorectal cancers or other HNPCC associated tumors, regardless of age
    • Colorectal cancer with MSI-H histology (see below) diagnosed before age 60 years
    • Colorectal cancer diagnosed in one or more first degree relatives with an HNPCC related tumor, with one of the cancers being diagnosed before age 50 years
    • Colorectal cancer diagnosed in 2 or more first or second degree relatives with HNPCC related tumors, regardless of age (J Natl Cancer Inst 2004;96:261)
  • Recommended screening for patients with Lynch syndrome:
    • Full colonoscopy every 1 - 2 years beginning at age 20 - 25 years
    • Annual screening for endometrial cancer beginning at age 25 - 35
    • Annual urinalysis and cytologic examination beginning at age 25
    • Annual skin surveillance and upper GI endoscopy beginning at age 35 when gastric cancer is part of the family spectrum (JAMA 2006;296:1507)
    • At colonscopic screening, patients have similar rate of adenomas as nonsyndrome patients but much higher incidence of carcinoma (Gastroenterology 2006;130:1995)
  • Germline testing for mutations can be performed
  • Microsatellite Instability testing of tumor specimens via PCR is widely utilized; this typically consists of a panel of 5 mono / dinucleotide repeats which are analyzed, and a shift in PCR product size of tumor versus normal indicates instability; designation of MSI-H requires instability in at least 30% of examined loci
  • Immunohistochemical testing panel for 4 MMR proteins (MLH1, MSH2, PMS2, MSH6) is widely utilized
  • BRAF V600E mutation analysis may be performed on cases with loss of MLH1 and PMS2 IHC staining: if mutation is present, then Lynch syndrome is virtually excluded
  • MLH1 gene promoter hypermethylation may be utilized to determine sporadic versus Lynch syndrome related colon cancers
Prognostic factors
  • Syndromic cancers have better survival than nonsyndromic
Case reports
Gross description
  • Usually proximal colon; 18% multiple and 40% metachronous (multiple separate occurrences)
Microscopic (histologic) description
  • Tumoral features suggestive of MSI-H etiology include: tumor infiltrating lymphocytes and peritumoral lymphocytes, Crohn's-like lymphoid reaction, mucinous features, medullary features, tumoral heterogeneity and absence of dirty necrosis
Negative stains
  • Defective mismatch repair genes can be reliably detected (negative staining) by immunohistochemistry (Am J Clin Pathol 2004;122:389, N Engl J Med 2005;352:1851)
    • Loss of only PMS2 staining is suggestive of PMS2 mutation
    • Loss of only MSH6 staining is suggestive of MSH6 mutation
    • Loss of MLH1 and PMS2 staining may be seen in MLH1 mutation (although sporadic colon cancers may also have this profile; if this profile is observed, follow up with BRAF V600E mutation analysis or MLH1 hypermethylation studies is warranted)
    • Loss of MSH2 and MSH6 staining may be seen in MSH2 mutation
Molecular / cytogenetics description
  • Defect in mismatch repair genes (caretaker genes that proofread DNA replication): typically MLH1 or MSH2, while MSH6 and PMS2 are less common (Gastroenterology 2006;130:312)
  • Rarely due to EPCAM mutation, germline promoter hypermethylation of MLH1, inactivation of CHEK2 (cell cycle checkpoint kinase 2)
  • Associated with microsatellite instability (MSI; microsatellites are dinucleotide repeat sequences, such as (CA)n, normally present in human genome), although MSI is not specific (World J Gastroenterol 2006;12:4745)
Board review style question #1
What is the most common hereditary colorectal cancer syndrome?

  1. Familial adenomatous polyposis
  2. Juvenile polyposis
  3. Lynch syndrome
  4. MUTYH associated polyposis
Board review style answer #1
C. Lynch syndrome

Comment Here

Reference: Lynch syndrome
Board review style question #2
Lynch syndrome usually arises from a germline mutation in a gene coding for a mismatch repair protein. A germline mutation in which of the following genes could also cause Lynch syndrome?

  1. BRAF
  2. CDH1
  3. EPCAM
  4. MUTYH
Board review style answer #2

Comment Here

Reference: Lynch syndrome
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