An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Manon Suerink, Mar Rodríguez-Girondo, Heleen M van der Klift, Chrystelle Colas, Laurence Brugieres, Noémie Lavoine, Marjolijn Jongmans, Gabriel Capellá Munar, D Gareth Evans, Michael P Farrell, Maurizio Genuardi, Yael Goldberg, Encarna Gomez-Garcia, Karl Heinimann, Jessica I Hoell, Stefan Aretz, Kory W Jasperson, Inbal Kedar, Mitul B Modi, Sergey NikolaevTheo A M van Os, Tim Ripperger, Daniel Rueda, Leigha Senter, Wenche Sjursen, Lone Sunde, Christina Therkildsen, Maria G Tibiletti, Alison H Trainer, Yvonne J Vos, Anja Wagner, Ingrid Winship, Katharina Wimmer, Stefanie Y Zimmermann, Hans F Vasen, Christi J van Asperen, Jeanine J Houwing-Duistermaat, Sanne W Ten Broeke, Maartje Nielsen

8 Citationer (Scopus)


PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias.

METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level.

RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women.

CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.

TidsskriftGenetics in medicine : official journal of the American College of Medical Genetics
Udgave nummer12
Sider (fra-til)2706-2712
Antal sider7
StatusUdgivet - dec. 2019


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