TY - JOUR
T1 - An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome
AU - Suerink, Manon
AU - Rodríguez-Girondo, Mar
AU - van der Klift, Heleen M
AU - Colas, Chrystelle
AU - Brugieres, Laurence
AU - Lavoine, Noémie
AU - Jongmans, Marjolijn
AU - Munar, Gabriel Capellá
AU - Evans, D Gareth
AU - Farrell, Michael P
AU - Genuardi, Maurizio
AU - Goldberg, Yael
AU - Gomez-Garcia, Encarna
AU - Heinimann, Karl
AU - Hoell, Jessica I
AU - Aretz, Stefan
AU - Jasperson, Kory W
AU - Kedar, Inbal
AU - Modi, Mitul B
AU - Nikolaev, Sergey
AU - van Os, Theo A M
AU - Ripperger, Tim
AU - Rueda, Daniel
AU - Senter, Leigha
AU - Sjursen, Wenche
AU - Sunde, Lone
AU - Therkildsen, Christina
AU - Tibiletti, Maria G
AU - Trainer, Alison H
AU - Vos, Yvonne J
AU - Wagner, Anja
AU - Winship, Ingrid
AU - Wimmer, Katharina
AU - Zimmermann, Stefanie Y
AU - Vasen, Hans F
AU - van Asperen, Christi J
AU - Houwing-Duistermaat, Jeanine J
AU - Ten Broeke, Sanne W
AU - Nielsen, Maartje
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - bMMRD
KW - colon cancer risk
KW - HNPCC
KW - MSH6
KW - PMS2
UR - http://www.scopus.com/inward/record.url?scp=85067855155&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0577-z
DO - 10.1038/s41436-019-0577-z
M3 - Journal article
C2 - 31204389
SN - 1098-3600
VL - 21
SP - 2706
EP - 2712
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 12
ER -