Canadian consensus for the assessment and testing of Lynch syndrome

Abstract

Background: Lynch syndrome (LS) 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. Ascertainment, assessment and testing of LS individuals is complex. A Canadian national guideline is needed to ensure equitable access to patient care across the country.

Methods: The Canadian Lynch Syndrome (CDN-LS) working group was formed in 2021, consisting of 37 multidisciplinary LS experts and patient partners. To formulate consensus statements, a national environmental scan, Canadian clinical survey and literature review were undertaken. The e-Delphi method was used to reach consensus statements among the CDN-LS group.

Results: The CDN-LS group voted on 21 statements, and 18 statements were adopted with over 80% agreement, including 16 statements that had over 90% agreement. These statements provide comprehensive guidelines on universal MMR reflex testing, cascade tumour testing (MLH1 promoter methylation, BRAF, somatic MMR), germline testing, therapeutics and patient advocacy.

Conclusion: This is the first comprehensive Canadian guideline for LS providing guidance to genetic specialists, laboratories, primary care providers and healthcare providers caring for patients with LS. It is endorsed by the Canadian College of Medical Genetics and the Canadian Association of Genetic Counsellors. The consensus statements are presented as a model for standard of care that improves equitable access to health services for LS across the country. Future work should include a national consensus on LS surveillance, with a goal to harmonise LS care across all provincial and territorial healthcare authorities.

Keywords: Disease Management; Gastrointestinal Diseases; Genetic Counselling; Genetic Testing; Molecular Diagnostic Techniques.

Figure 1. Flow chart for Lynch syndrome (LS) testing. Mismatch repair (MMR) genes include MLH1, MSH2, MSH6, PMS2 and EPCAM. ∧Reference to Canadian Lynch Syndrome (CDN-LS) group statement. ¹Consider MLH1 hypermethylation ±BRAF V600E as somatic cause. ²BRAF for colorectal tumours only. ³Cascade reflex MLH1 promoter methylation is recommended on all colorectal cancers/endometrial cancers (CRC/EC) and BRAF V600E testing on all CRCs that have MLH1 protein deficiency (CDN-LS statements C8–C9). ⁴May be considered as a first-tier test in lieu of germline alone to expedite. IHC, immunohistochemistry; LOH, loss of heterozygosity; LPV, likely pathogenic variant; MGPT, multi-gene panel testing; MSI-H, microsatellite instability-high; PV, pathogenic variant; VUS, variant of uncertain significance.