An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndromeSuerink, M., Rodriguez-Girondo, M., van der Klift, H. M., Colas, C., Brugieres, L., Lavoine, N., Jongmans, M., Capella Munar, G., Evans, D. G., Farrell, M. P., Genuardi, M., Goldberg, Y., Gomez-Garcia, E., Heinimann, K., Hoell, J., Aretz, S., Jasperson, K. W., Kedar, I., Modi, M. B., Nikolaev, S., van Os, T. A. M., Ripperger, T., Rueda, D., Senter, L., Sjursen, W., Sunde, L., Therkildsen, C., Tibiletti, M. G., Trainer, A. H., Vos, Y. J., Wagner, A., Winship, I., Wimmer, K., Zimmermann, S. Y., Vasen, H. F., van Asperen, C. J., Houwing-Duistermaat, J. J., ten Broeke, S. W. & Nielsen, M., Dec-2019, In : Genetics in Medicine. 21, 12, p. 2706-2712 7 p.
Research output: Contribution to journal › Article › Academic › peer-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.
|Number of pages||7|
|Journal||Genetics in Medicine|
|Publication status||Published - Dec-2019|
- HNPCC, colon cancer risk, PMS2, MSH6, bMMRD, DNA MISMATCH REPAIR, GERMLINE MUTATIONS, MICROSATELLITE INSTABILITY, FREQUENCY, AGE, SURVEILLANCE, CRITERIA, PHENOTYPE, FAMILIES, BREAST