- Prevalence: 1 in 279 people carry defective mismatch repair (MMR) genes.
- The most common inherited colon cancer syndrome
- Accounts for 2%–4% of colorectal cancers
- Increased risk for endometrial cancer and many other cancers
- Malignancies occur earlier than in general population (5th decade).
- General lifetime cancer risks in Lynch syndrome (LS) (approximate midpoints of broad ranges):
- Colorectal cancer: 50% (right colon > left colon)
- Endometrial cancer: 38%
- Ovarian cancer: 19%
- Stomach cancer: 7%
- Sex ratio: women = men
Lynch syndrome patients inherit one or more mutant MMR genes and the respective normal allele/alleles; the 2nd allele then becomes mutated or loses function by epigenetic silencing so often that the inheritance pattern is effectively autosomal dominant.
- MMR genes that can become mutated: MLH1, MSH2 (an EpCAM (epithelial cell adhesion molecule) gene mutation can also cause loss), MSH6, and PMS2
- Mutations then occur at rates up to 1,000 times higher than normal, mostly in regions of repetitive sequences called microsatellites.
- The protein products of mismatch repair (MMR) genes are important in “spell-checking” DNA during duplication by detecting and repairing DNA defects.
- Loss of MMR activity causes an accumulation of DNA replication errors, particularly in repetitive sequences (“tandem repeats”).
- Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs.
- A cancer-driver mutation is eventually created by one of the uncorrected errors made during DNA replication.
- MMR mutations can also occur as sporadic somatic mutations.
Pathogenesis and Pathology
- Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma.
- The MMR pathway of colon carcinogenesis is the 2nd-most common pathway of colorectal cancer (CRC), after the adenoma-carcinoma pathway of colon carcinogenesis.
- Characteristics of CRCs arising via the MMR (MSI-H) pathway: tend to show more mucinous features and reactive tumor-infiltrating lymphocytes
- Characteristics of endometrial carcinomas in LS: increased frequency of non-endometrioid carcinoma histologies
- Slightly higher number of adenomatous polyps than the general population, but a higher rate of progression to CRC than typical polyps.
Clinical Presentation and Diagnosis
- Patients are asymptomatic until they develop malignancy.
- Colorectal adenocarcinomas:
- LS manifests with only a low or slightly higher-than-usual number of polyps.
- Right-side carcinomas (more common): iron deficiency anemia due to bleeding
- Left-sided carcinomas: changes in bowel habits or stool caliber
- Endometrial carcinomas: abnormal endometrial bleeding
- 1 or more germline mutations in the mismatch repair (MMR) genes or EPCAM gene are needed for a definitive diagnosis of Lynch syndrome.
- 2 pathways are used to establish the diagnosis: Test the tumor first, or base testing on family history.
- Suspect Lynch syndrome in any patient who has:
- CRC prior to 50 years of age, or if more than 1 CRC
- Endometrial carcinoma < 60 years of age
- A 1st-degree relative with known LS
- Fulfilled accepted criteria for LS (Amsterdam criteria or Bethesda guidelines)
- Amsterdam II criteria (poor sensitivity, suspect LS if the following criteria are met):
- 3 or more relatives (at least 1 first-degree) have LS–associated cancers; familial adenomatous polyposis (FAP) excluded.
- LS–associated cancers involving at least 2 generations
- 1 or more cancers diagnosed before the age of 50 years
- Bethesda guidelines, revised (better sensitivity and specificity than Amsterdam criteria):
- CRC diagnosed < 50 years of age
- 2 or more LS-associated cancers
- CRC with MSI-H–like histology in patient < 60 years of age
- CRC in patient with a 1st-degree relative with LS–associated cancer < 50 years
- CRC in patient with 2 1st-degree relatives with LS–associated cancer, any age
Surveillance and screening tests
- For CRC: annual colonoscopy starting at 20–25 years of age, or 2–5 years prior to the earliest age of CRC diagnosis in the family
- For endometrial cancer: annual endometrial biopsy, starting at 30 years of age
- Annual skin examinations to detect: sebaceous tumors (benign and malignant) and cutaneous keratoacanthomas associated with Muir-Torre syndrome (a variant of LS)
- Reproductive counseling: LS patients of reproductive age should be offered carrier testing.
- Total abdominal colectomy instead of segmental resection for CRC
- If rectal cancer: total proctocolectomy
For endometrial cancer:
- Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) if cancer diagnosed
- Prophylactic TAHBSO when childbearing is complete
- Estrogen-progestin contraceptives reduce risk of endometrial and ovarian cancers
- Aspirin: may reduce the risk of CRC
- Pembrolizumab or nivolumab
- Used in MSI-H–/MMR–deficient tumors
- FAP: presents with hundreds of adenomatous polyps and typically results in CRC in the distal colon. Lynch syndrome typically manifests with CRC in the proximal colon and only a low number of polyps. Genetic testing can distinguish between the 2 conditions.
- Familial colorectal cancer type X (FCCTX): Amsterdam I criteria are met but the tumors lack the MSI seen in LS. No increased risk of other LS–associated cancers.
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