@article{dc8df26c4c6649e08976bb1a7327d59c,
title = "An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome",
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.",
keywords = "HNPCC, colon cancer risk, PMS2, MSH6, bMMRD, DNA MISMATCH REPAIR, GERMLINE MUTATIONS, MICROSATELLITE INSTABILITY, FREQUENCY, AGE, SURVEILLANCE, CRITERIA, PHENOTYPE, FAMILIES, BREAST",
author = "Manon Suerink and Mar Rodriguez-Girondo and {van der Klift}, {Heleen M.} and Chrystelle Colas and Laurence Brugieres and Noemie Lavoine and Marjolijn Jongmans and {Capella Munar}, Gabriel and Evans, {D. Gareth} and Farrell, {Michael P.} and Maurizio Genuardi and Yael Goldberg and Encarna Gomez-Garcia and Karl Heinimann and Jessica Hoell and Stefan Aretz and Jasperson, {Kory W.} and Inbal Kedar and Modi, {Mitul B.} and Sergey Nikolaev and {van Os}, {Theo A. M.} and Tim Ripperger and Daniel Rueda and Leigha Senter and Wenche Sjursen and Lone Sunde and Christina Therkildsen and Tibiletti, {Maria G.} and Trainer, {Alison H.} and Vos, {Yvonne J.} and Anja Wagner and Ingrid Winship and Katharina Wimmer and Zimmermann, {Stefanie Y.} and Vasen, {Hans F.} and {van Asperen}, {Christi J.} and Houwing-Duistermaat, {Jeanine J.} and {ten Broeke}, {Sanne W.} and Maartje Nielsen",
note = "Funding Information: 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{\textquoteright}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 Medactie.com for help with editing of this paper. This work was supported by a grant from the Dutch Cancer Society (KWF UL 2012–5155). Funding Information: 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. Publisher Copyright: {\textcopyright} 2019, American College of Medical Genetics and Genomics.",
year = "2019",
month = dec,
doi = "10.1038/s41436-019-0577-z",
language = "English",
volume = "21",
pages = "2706--2712",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "12",
}