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Open Access 01-10-2018 | Original Article

SNP association study in PMS2-associated Lynch syndrome

Authors: Sanne W. ten Broeke, Fadwa A. Elsayed, Lisa Pagan, Maran J. W. Olderode-Berends, Encarna Gomez Garcia, Hans J. P. Gille, Liselot P. van Hest, Tom G. W. Letteboer, Lizet E. van der Kolk, Arjen R. Mensenkamp, Theo A. van Os, Liesbeth Spruijt, Bert J. W. Redeker, Manon Suerink, Yvonne J. Vos, Anja Wagner, Juul T. Wijnen, E. W. Steyerberg, Carli M. J. Tops, Tom van Wezel, Maartje Nielsen

Published in: Familial Cancer | Issue 4/2018

Abstract

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2–3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5–4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.

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Title: SNP association study in PMS2-associated Lynch syndrome
Authors: Sanne W. ten Broeke
Fadwa A. Elsayed
Lisa Pagan
Maran J. W. Olderode-Berends
Encarna Gomez Garcia
Hans J. P. Gille
Liselot P. van Hest
Tom G. W. Letteboer
Lizet E. van der Kolk
Arjen R. Mensenkamp
Theo A. van Os
Liesbeth Spruijt
Bert J. W. Redeker
Manon Suerink
Yvonne J. Vos
Anja Wagner
Juul T. Wijnen
E. W. Steyerberg
Carli M. J. Tops
Tom van Wezel
Maartje Nielsen
Publication date: 01-10-2018
Publisher: Springer Netherlands
Published in: Familial Cancer / Issue 4/2018
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-017-0061-3

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