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. 2018 Oct;17(4):507-515.
doi: 10.1007/s10689-017-0061-3.

SNP association study in PMS2-associated Lynch syndrome

Sanne W Ten Broeke  1 , Fadwa A Elsayed  2 , Lisa Pagan  3 , Maran J W Olderode-Berends  4 , Encarna Gomez Garcia  5 , Hans J P Gille  6 , Liselot P van Hest  6 , Tom G W Letteboer  7 , Lizet E van der Kolk  8 , Arjen R Mensenkamp  9 , Theo A van Os  10 , Liesbeth Spruijt  9 , Bert J W Redeker  10 , Manon Suerink  3 , Yvonne J Vos  4 , Anja Wagner  11 , Juul T Wijnen  3 , E W Steyerberg  12 , Carli M J Tops  3 , Tom van Wezel  2 , Maartje Nielsen  3
Affiliations

SNP association study in PMS2-associated Lynch syndrome

Sanne W Ten Broeke et al. Fam Cancer. 2018 Oct.

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.

Keywords: Cancer risk; Colorectal cancer; Lynch syndrome; Modifiers; PMS2; SNP.

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Conflict of interest statement

The authors report no conflict of interests.

Figures

Fig. 1
Fig. 1
Forest plot of HRs for all SNPs. rs5934683 lies on the X chromosome and was therefore stratified for gender. *SNPs previously associated with increased risk in MLH1 mutation carriers. #Reference category: homozygous for risk allele (due to low number of homozygous carriers of the non-risk allele). HR Hazard ratio
Fig. 2
Fig. 2
Forest plot of HRs for rs1321311. p = 0.005 for males. HR Hazard ratio
Fig. 3
Fig. 3
Forest plot of HRs for rs3802842 and rs16892766. For the combination of the two SNPs, the plotted HR represents a comparison for carriers of three vs. no risk alleles. HR Hazard ratio
Fig. 4
Fig. 4
Kaplan Meier survival curve for PRS2. This plot compares curves for the lowest, the two middle and the highest quartile of the PRS. PRS2 is based on hazard ratios from the current study. HR Hazard ratio, PRS polygenic risk score
See this image and copyright information in PMC

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