Lynch syndrome assessment and testing: Canadian consensus recommendations

Lynch syndrome is the most common inherited cause of colorectal and endometrial cancer. It is an autosomal dominant cancer predisposition syndrome caused by a germline pathogenic variant, or epigenetic silencing, of a mismatch repair (MMR) gene, leading to a wide cancer spectrum with gene-specific penetrance. Approximately one in 279 individuals have Lynch syndrome, although this figure may be an underestimate.1Lynch syndrome MLH1 and MSH2/EPCAM carriers have the highest lifetime risk of colorectal cancer, with lower risks observed in MSH6 and PMS2 carriers. Endometrial cancer is the most penetrant cancer among females with MSH2/EPCAM, MSH6 and PMS2 pathogenic variants, and the second most common cancer in those with MLH1 pathogenic variants.1Identifying patients with Lynch syndrome is important because their lifetime risk of colorectal cancer is 80%, and up to 60% for endometrial cancer. Other primary cancers associated with Lynch syndrome include gastric, ovarian, small bowel, urothelial (ureter, renal pelvis and bladder), prostate, biliary tract, pancreatic, adrenocortical, brain (glioblastoma), sebaceous gland adenomas and keratoacanthomas.2 Early detection of Lynch syndrome is vital as patients can be enrolled in cancer reduction strategies through chemoprophylaxis, risk-reducing surgery and cancer surveillance.3The Canadian Lynch Syndrome (CDN-LS) working group has now released the first comprehensive Canadian consensus recommendations for Lynch syndrome. The 18 recommendations were developed because determination, assessment and testing of individuals with Lynch syndrome is complex and a Canadian national guideline is needed to ensure equitable access to patient care across the country.1The new guidelines provide a standard of care for the assessment of Lynch syndrome in Canada, as well as patient advocacy and therapeutics recommendations. Eleven recommendations address Lynch syndrome diagnostic (testing) pathways; four address patient advocacy across Canada; two address therapeutics and one addresses screening guidelines.1Lynch syndrome: two therapeutic recommendationsUnless clinically contraindicated, hormone replacement therapy with systemic estrogen is recommended for premenopausal women with Lynch syndrome after preventive hysterectomy and bilateral salpingo-oophorectomy, to reduce the long-term negative effects of premature oophorectomy. Hormone replacement should be continued until the age of natural menopause (average natural age is 51 years). This recommendation should be discussed with the patient’s primary care provider and/or gynecologist. An important consideration to this recommendation is the evidence of protection against colorectal cancer from hormone replacement therapy.Daily acetylsalicylic acid (ASA) treatment can be discussed with patients with Lynch syndrome, acknowledging that there is only limited knowledge of the optimal dose and timing to begin and end treatment. A minimum dose of 81 mg daily may be considered after discussion of potential contraindications with the primary physician. Research was originally conducted on ASA 600 mg daily over two years, with a reduction observed in the incidence of colorectal cancer that becomes apparent five years after treatment. Ongoing investigation of the optimal dosage continues. The Colorectal Adenoma/Carcinoma Prevention Programme showed a significant reduction in the incidence of colorectal cancer and nonsignificant reductions of other Lynch syndrome-associated tumours among those individuals treated with ASA 600 mg daily for at least two years versus placebo. The protective effect persisted for over a decade for individuals who took ASA for two years.1The new recommendations can be used as a guideline to streamline policies and practices for providing care to patients with Lynch syndrome across Canada. The recommendations are endorsed by the Canadian College of Medical Genetics and the Canadian Association of Genetic Counsellors. They are designed to provide valuable guidance to genetic specialists, laboratories, primary care providers and healthcare professionals who care for patients with Lynch syndrome.References:Aronson M, Palma L, Semotiuk K, et al. Canadian consensus for the assessment and testing of Lynch syndrome. J Med Genet 2025 Mar 12:jmg-2024-110465. Online ahead of print. (accessed April 1, 2025). Bhattacharya P, Leslie SW, McHugh TW. Lynch syndrome (hereditary nonpolyposis colorectal cancer). StatPearls June 8, 2024. (accessed April 1, 2025).Georgiou D, Monje-Garcia L, Miles T, et al. A focused clinical review of Lynch syndrome. Cancer Manag Res 2023:15:67-85. (accessed April 1, 2025).

Lynch syndrome assessment and testing: Canadian consensus recommendations

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