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

Specialty Areas:
Date: July 17, 2019
Authors:
Alison H. Trainer, Anja Wagner, Christi J. van Asperen, Christina Therkildsen, Chrystelle Colas, D. Gareth Evans, Daniel Rueda, Encarna Gomez-Garcia, Gabriel Capellá Munar, Hans F. Vasen, Heleen M. van der Klift, Inbal Kedar, Ingrid Winship, Jeanine J. Houwing-Duistermaat, Jessica I. Hoell, Karl Heinimann, Katharina Wimmer, Kory W. Jasperson, Laurence Brugieres, Leigha Senter, Lone Sunde, Maartje Nielsen, Manon Suerink, Maria G. Tibiletti, Marjolijn Jongmans, Mar Rodríguez-Girondo, Maurizio Genuardi, Michael P. Farrell, Mitul B. Modi, Noémie Lavoine, Sanne W. ten Broeke, Sergey Nikolaev, Stefan Aretz, Stefanie Y. Zimmermann, Theo A. M. van Os, Tim Ripperger, Wenche Sjursen, Yael Goldberg, Yvonne J. Vos
Journal: Genetics in Medicine
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Abstract

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.