Lynch Syndrome

Order mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite-instability (MSI) testing for newly diagnosed colorectal cancer. Universal tumor screening detects cases that age- and family-history criteria miss; Amsterdam and revised Bethesda criteria have important sensitivity and specificity limitations. PubMed+1PubMedHereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI BookshelfPubMedGenetics of Colorectal Cancer (PDQ®) - PDQ Cancer Information Summaries - NCBI Bookshelf

Apply the same tumor-testing framework to endometrial carcinoma when feasible. Tumor-testing strategies are established for colorectal and endometrial cancers, whereas evidence for routine application to other Lynch-spectrum tumors is more limited. PubMedPubMedLynch Syndrome - GeneReviews® - NCBI Bookshelf

Trigger genetics referral and germline testing when tumor findings suggest inherited MMR deficiency, when a patient has a personal or family pattern of Lynch-spectrum cancers, or when the clinical probability remains concerning despite nondiagnostic tumor testing. Lynch-associated tumors include colorectal, endometrial, ovarian, gastric, small-bowel, pancreatic, biliary tract, upper urinary tract, bladder, prostate, brain, and sebaceous skin tumors. PubMed+2PubMedHereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI BookshelfCDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDCPubMedDiagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

MMR IHC identifies loss of the MLH1, MSH2, MSH6, or PMS2 protein products; MSI testing identifies the genomic instability caused by MMR dysfunction. Either abnormality establishes MMR deficiency but does not by itself establish Lynch syndrome, because sporadic colorectal cancers can be MSI-high or MMR-deficient through acquired MLH1 methylation. PubMed+1PubMedTumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC) - PMCPubMedGenetic Testing for Lynch Syndrome, an Inherited Cancer of the Bowel, Endometrium, and Ovary

In colorectal cancer with MLH1/PMS2 loss, a positive BRAF V600E result supports a sporadic MLH1-deficient tumor. MLH1 promoter methylation similarly supports acquired MLH1 silencing; when BRAF is negative and MLH1 methylation is absent, proceed to germline testing for Lynch syndrome. PubMed+2PubMedLynch Syndrome - GeneReviews® - NCBI BookshelfPubMedGenetic Testing for Lynch Syndrome, an Inherited Cancer of the Bowel, Endometrium, and OvaryPubMedA Review of Hereditary Colorectal Cancers - StatPearls - NCBI Bookshelf

Do not extrapolate BRAF triage to endometrial cancer or other tumors. For noncolorectal tumors with MLH1 loss, MLH1 promoter methylation is the relevant tumor assay in the supplied testing framework. PubMedPubMedLynch Syndrome - GeneReviews® - NCBI Bookshelf

Interpret MSI and IHC as complementary rather than interchangeable when suspicion is high. MSI sensitivity is reported as lower for MSH6 and PMS2 carriers than for MLH1 and MSH2 carriers, making IHC particularly useful in the MSH6/PMS2 branch. PubMedPubMedTumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC) - PMC

Confirm Lynch syndrome by identifying a germline pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM-associated MSH2 pathway disease after pretest counseling. Lynch syndrome is autosomal dominant; once the familial pathogenic variant is known, offer targeted testing to biologic relatives rather than broad, untargeted testing. NEJM+1NEJMCancer Risk with the Lynch Syndrome PMS2 Gene | NEJM ClinicianPubMedHereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI Bookshelf

Use the family's identified variant to distinguish relatives who need Lynch-specific prevention from those who do not carry that familial pathogenic variant. Cascade testing is clinically consequential because intensive colonoscopic surveillance and gynecologic risk-reduction decisions should be concentrated in confirmed carriers. CDC+1CDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDCPubMedLynch Syndrome - GeneReviews® - NCBI Bookshelf

Treat gene identity as a risk modifier rather than a reason to abandon surveillance. MSH6 and PMS2 variants generally confer lower risks of colorectal and other Lynch-associated malignancies than MLH1 or MSH2 variants, and PMS2 variants are associated with reduced endometrial and ovarian risk, but affected carriers still require individualized prevention planning. NEJM+1NEJMCancer Risk with the Lynch Syndrome PMS2 Gene | NEJM ClinicianPubMedHereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI Bookshelf

Schedule colonoscopy every 1 to 2 years for confirmed Lynch syndrome carriers. The CDC advises beginning 2 to 5 years before the earliest colorectal cancer diagnosis in the family; European guidance cited in the evidence base uses 1- to 2-year intervals and gene-specific starting ages. nice org uk+1nice org uk[PDF] national institute for health and care - NICECDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDC

Where using the cited gene-stratified protocol, begin at age 25 years for MLH1, MSH2, or EPCAM pathogenic-variant carriers and at age 30 years for MSH6 or PMS2 carriers; continue to age 75 years, then reassess. Earlier initiation is warranted when the family’s earliest colorectal cancer occurred before the applicable age threshold. nice org uknice org uk[PDF] national institute for health and care - NICE

Remove polyps during colonoscopy rather than treating surveillance as diagnostic observation alone. Lynch-associated colorectal neoplasia is often right-sided and may include flat premalignant lesions, supporting meticulous total-colon examination. CDC+1CDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDCPubMedA Review of Hereditary Colorectal Cancers - StatPearls - NCBI Bookshelf

Discuss aspirin chemoprevention as a separate shared decision rather than substituting it for colonoscopy. Long-term CAPP2 follow-up is cited as evidence for cancer prevention with aspirin in Lynch syndrome, but the excerpts do not establish a U.S. standard dose; a cited NICE scope notes that 75 to 300 mg is commonly offered outside the trial context. NEJM+2NEJMCancer Risk with the Lynch Syndrome PMS2 Gene | NEJM ClinicianNatureRisk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report | Genetics in Medicinenice org uk[PDF] national institute for health and care - NICE

For carriers with a uterus and ovaries, discuss risk-reducing hysterectomy with bilateral salpingo-oophorectomy after childbearing is complete. In Lynch syndrome, prophylactic surgery has evidence of preventing endometrial and ovarian cancer and remains the most definitive risk-reducing option. NEJM+2NEJMProphylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome | New England Journal of MedicineNatureLynch Syndrome and Gynecological Cancer Prevention | Cancer Genetics | Oncology and Carcinogenesis | Health sciences | Topics | Nature IndexNatureRisk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report | Genetics in Medicine

Do not present transvaginal ultrasound and endometrial sampling as equivalent substitutes for surgery. Annual transvaginal ultrasound and endometrial sampling have variable sensitivity and adherence, and public-health guidance emphasizes that no simple, reliable screening test exists for gynecologic cancers in Lynch syndrome. Nature+1NatureLynch Syndrome and Gynecological Cancer Prevention | Cancer Genetics | Oncology and Carcinogenesis | Health sciences | Topics | Nature IndexCDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDC

Until definitive surgery, instruct patients to report abnormal uterine bleeding and other gynecologic cancer symptoms promptly rather than waiting for a surveillance interval. Symptom-triggered evaluation is particularly important because endometrial cancer is a major Lynch-associated malignancy. PubMed+1PubMedHereditary Nonpolyposis Colon Cancer (Lynch Syndrome) - StatPearls - NCBI BookshelfCDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDC

For extracolonic disease, make surveillance and symptom review gene- and family-history directed rather than applying a uniform battery of low-yield tests. Consider upper gastrointestinal evaluation in patients whose pedigree or clinical context suggests gastric cancer risk, and review hematuria or urinary tract symptoms carefully in MSH2 carriers because urinary tract cancer risk is increased in that subgroup. ScienceDirect+2ScienceDirectClinical Factors Associated With Gastric Cancer in Individuals With Lynch Syndrome - ScienceDirectScienceDirectUrinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations - ScienceDirectCDCManaging Risk for Cancers Related to Lynch Syndrome | Hereditary Colorectal (Colon) Cancer | CDC