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

Maurizio Genuardi, M Suerink, M Rodríguez-Girondo, der Klift HM van, C Colas, L Brugieres, N Lavoine, M Jongmans, GC Munar, DG Evans, MP Farrell, Y Goldberg, E Gomez-Garcia, K Heinimann, JI Hoell, S Aretz, KW Jasperson, I Kedar, MB Modi, S NikolaevOs TAM van, T Ripperger, D Rueda, L Senter, W Sjursen, L Sunde, C Therkildsen, MG Tibiletti, AH Trainer, YJ Vos, A Wagner, I Winship, K Wimmer, SY Zimmermann, HF Vasen, Asperen CJ van, JJ Houwing-Duistermaat, Broeke SW Ten, M Nielsen

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer 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.
Lingua originaleEnglish
pagine (da-a)1-7
Numero di pagine7
RivistaGenetics in Medicine
Stato di pubblicazionePubblicato - 2019


  • colorectal cancer

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