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



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.


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.


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.


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.

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We acknowledge Susan E. Andrew (Department of Medical Genetics, University of Alberta, Edmonton, Canada) and Kate Green (Division of Evolution and Genomic Medicine, Manchester Academic Health Science Centre [MAHSC], University of Manchester, St Mary’s Hospital, Manchester, UK) for providing data, and the Care for CMMRD (C4CMMRD) Consortium for providing data and a platform to discuss this study. The authors thank for help with editing of this paper. This work was supported by a grant from the Dutch Cancer Society (KWF UL 2012–5155).

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Correspondence to Manon Suerink MD.

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D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). K.W.J. is a full-time employee of Ambry Genetics. S.N. is funded by Foundation ARC 2017, Foundation Gustave Roussy, and Swiss Cancer League KFC-3985-08-2016. The other authors declare no conflicts of interest.

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  • colon cancer risk
  • PMS2
  • MSH6
  • bMMRD