SNP association study in PMS2-associated Lynch syndrome
Ten Broeke, Sanne W.; Elsayed, Fadwa A.; Pagan, Lisa; Olderode-Berends, Maran J W; Garcia, Encarna Gomez; Gille, Hans J J P; van Hest, Liselot P.; Letteboer, Tom G.W.; Van Der Kolk, Lizet E.; Mensenkamp, Arjen R.; Van Os, Theo A.; Spruijt, Liesbeth; Redeker, Bert J W; Suerink, Manon; Vos, Yvonne J.; Wagner, Anja; Wijnen, Juul T.; Steyerberg, Ewout W.; Tops, Carli M J; van Wezel, Tom; Nielsen, Maartje
(2018) Familial Cancer, volume 17, issue 4, pp. 507 - 515
(Article)
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
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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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Keywords: Cancer risk, Colorectal cancer, Lynch syndrome, Modifiers, PMS2, SNP, Genetics, Oncology, Genetics(clinical), Cancer Research
ISSN: 1389-9600
Publisher: Springer Netherlands
Note: Funding Information: Funding This work was supported by the Dutch Cancer Society (Grant: UL-2012-5515). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: The authors would like to thank Ruud van der Breggen (LUMC) for technical support. Writing assistance: The final manuscript was edited by Medactie, funded by the Dutch Cancer Society. The authors report no conflict of interests. Publisher Copyright: © 2017, The Author(s).
(Peer reviewed)
