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

Manon Suerink*, Mar Rodriguez-Girondo, Heleen M. van der Klift, Chrystelle Colas, Laurence Brugieres, Noemie Lavoine, Marjolijn Jongmans, Gabriel Capella Munar, D. Gareth Evans, Michael P. Farrell, Maurizio Genuardi, Yael Goldberg, Encarna Gomez-Garcia, Karl Heinimann, Jessica 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)2706-2712
Number of pages7
JournalGenetics in Medicine
Issue number12
Publication statusPublished - Dec 2019


  • colon cancer risk
  • PMS2
  • MSH6
  • bMMRD
  • AGE

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