Abstract 1238: International comparison of cancer risks for Lynch syndrome

Abstract

Abstract Aims: The International Mismatch Repair Consortium (IMRC) was formed in 2010 and comprises major worldwide consortia involved in the research and/or clinical treatment of Lynch syndrome (cancer predisposition caused by inherited mutations in mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2 and EPCAM); http://www.sphinx.org.au/imrc. The aim of this study was to determine cancer risks by geographic region. Methods: For each cancer, we estimated the age-specific cumulative risks (penetrance) and the hazard ratios compared to the average population risk. We used a modified segregation analysis and adjusted for any ascertainment of families given this is an analysis of prospective data. We estimated penetrance by: cancer sex, mismatch repair gene, type of mutation, and geographic region. Results: 43 investigators representing 53 different sites in 23 countries have submitted pedigree data. In total IMRC consists of 6,436 Lynch syndrome families (North America = 2,482, South America = 101, Europe = 3,307, Asia = 216, Australasia = 330). Of these, 2,214 were MLH1, 2,717 were MSH2, 1,118 were MSH6, 558 were PMS2, and 44 were EPCAM. The total number of distinct variants were 1,270 and the maximum size of families was 333 relatives. Of the distinct MMR variants submitted to the IMRC, 89% were classified as Class 4 (likely pathogenic) or 5 (pathogenic) by the InSiGHT Variant classification criteria (LOVD). Penetrance analyses were conducted only for the pathogenic or likely pathogenic variants. Preliminary analyses suggest that the risk of colorectal cancer to age 70 is highest for carriers in Australasia and North America and lowest for carriers in South America and Asia (Table 1). Conclusion: Preliminary results suggest that cancer risks for people with Lynch syndrome differ by geographic region, which is consistent with environmental modifiers for the disease and might justify region-specific screening guidelines. Risk (% to age 70) and hazard ratio (HR) of colorectal cancer by MMR gene and regionGeneRegionHR (95% CI)Risk MalesRisk FemalesMLH1Europe19 (14-26)50%32%MLH1Nth America32 (26-38)61%48%MLH1Australasia32 (22-46)68%55%MLH1Sth America6 (2-22)12%10%MLH1Asia7 (5-15)39%24%MSH2Europe14 (11-16)39%24%MSH2Nth America33 (28-40)61%50%MSH2Australasia36 (24-54)73%59%MSH2Sth America70 (10-490)82%75%MSH2Asia8 (5-17)21%15% Citation Format: Mark A. Jenkins, Jeanette Reece, Grant Lee, Aung K. Win, International Mismatch Repair Consortium. International comparison of cancer risks for Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1238.