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Lynch syndrome

From SNPedia

Lynch syndrome, the most common hereditary cause of colorectal cancer, is an autosomal dominant cancer-susceptibility syndrome. It is named after Dr. Henry Lynch, whose role was crucial in the clinical and scientific identification of the syndrome. Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC), a rather misleading name, as several other cancers also belong to the disease spectrum. Wikipedia Genomic testing for Lynch syndrome in all newly diagnosed patients with colorectal cancer is recommended by the EGAPP Working Group, primarily to help "reduce morbidity and mortality" in the relatives of the ~3% of such patients likely to carry Lynch-associated mutations.

The genetic cause of Lynch syndrome began to unravel in 1993, when two major findings came together:

  • One was the report of genetic instability associated with replication errors in microsatellite sequences in a large percentage of tumours from Lynch syndrome patients. [PMID 8484121] [PMID 8505985] [PMID 8261393] [PMID 848412]
  • The other was the identification of two Lynch syndrome loci by linkage analysis, at chromosomes 2p and 3p. [PMID 7903889] [PMID 15528792] During 1994, the first germline mutations were found in two genes identified in those loci (MSH2 and MLH1), both being human homologs of the well-known mutS and mutL mismatch repair (MMR) genes of bacteria and yeast. Thus, deficient DNA mismatch repair was identified as the cause of Lynch syndrome. This functional inactivation of the DNA MMR genes is due to germline mutations as the first hit [PMID 8156592] [PMID 8252616] [PMID 8261515] [PMID 8145827] [PMID 8128251], followed by somatic inactivation of the second allele as the second hit. [PMID 7894494] [PMID 8613431] This second hit is usually a somatic mutation or loss of heterozygosity (LOH).

Genes identified in Lynch syndrome:

  • MLH1 and MSH2
    • These two genes include the vast majority of mutations found in Lynch syndrome cases. [PMID 15528792]
  • Other genes
    • An interstitial deletion at 3p21.3 resulting in the genetic fusion of MLH1 and ITGA9 has been reported in a Lynch syndrome family, presumably defining a novel subclass of Lynch syndrome patients. [PMID 19188145]
    • Several other genes in the MMR pathway have been screened over the years as well. Mutations in MLH3 and EXO1 have been found [PMID 11375940] but due to their low frequencies and type, mostly missense, they are not considered to be major players in Lynch syndrome. [PMID 12800209] [PMID 12517792] [PMID 18951442]

The percent of known Lynch syndrome disease-causing mutations that are tested by several companies is shown in the following table for four genes:

SNP % is based on # of magnitude 5+ SNPs on chip vs in SNPedia (unadjusted for mutation frequency)
Company & chip version MLH1 MSH2 MSH6 PMS2
23andMe v4
13% 25% 18% 10%
23andMe v5 20% 28% 38% 39%
Ancestry v2
73% 70% 68% 44%

The CDC states the following (here) as facts about Lynch syndrome (LS):

  • LS has an autosomal dominant inheritance pattern (only one copy of the mutation is needed to manifest the disease; first-degree relatives (parents, children, siblings) of an affected person have a 50% risk to inherit the mutation); other relatives (e.g., grandparents, aunts, uncles, cousins, nieces and nephews) are also at increased risk;
  • Among people with LS, lifetime risk for CRC ranges from approximately 20-80%, depending upon the mutation involved, the sex of the affected individual, and the population studied;
  • The mean age of onset of CRC in those with LS is approximately 45 years; and,
  • People with LS have an increased risk of other malignancies including those of the endometrium, ovary, urinary tract, gastric tract, small bowel, pancreas, and skin (sebaceous).

When should surveillance start for carriers of known Lynch syndrome mutations? Based on a study of over 1,000 such patients, a 2017 publication concludes colonoscopies should begin at age 25 years for those with MLH1 and MSH2 mutations and at age 30 years from those with MSH6 and PMS2 mutations. Gynecologic surveillance appeared appropriate starting at age 30 years for those with MSH2 mutations, 35 years for those with nontruncating MLH1 mutations, and age 40 years for those with MSH6 and truncating MLH1 mutations.[PMID 28065618OA-icon.png];[1]

Lynch syndrome is also the subject of a ClinGen Actionability recommendation.

A patient advocacy organization, AliveAndKickn.org, provides educational resources and maintains the HEROIC patient registry for Lynch syndrome patients.

news The authors say: "600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. The case for prescription of aspirin to this high-risk group is clear." All patients were carriers of Lynch Syndrome, a genetic anomaly that predisposes a person to developing colorectal cancer and a range of other solid organ cancers. At least one in 1,000 people carry this disorder that accounts for about one in 30 cases of bowel cancer.