SNP association study in PMS2-associated Lynch syndrome

• Published in: Familial cancer Vol. 17; no. 4; pp. 507 - 515
• Main Authors: ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J. W., Garcia, Encarna Gomez, Gille, Hans 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, E. W., Tops, Carli M. J., van Wezel, Tom, Nielsen, Maartje
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2018; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 8; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - mortality; Epidemiology; Female; Genetic disorders; Genetic Predisposition to Disease; Genetic variability; Genome-wide association studies; Genome-Wide Association Study; Genomes; Heterozygote; Human Genetics; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mismatch Repair Endonuclease PMS2 - genetics; MLH1 protein; MSH2 protein; MSH6 protein; Original; Original Article; Polymorphism; Polymorphism, Single Nucleotide; Studies; PMS2; SNP; Modifiers; Colorectal cancer; Lynch syndrome; Cancer risk
• ISSN: 1389-9600; 1573-7292
• DOI: 10.1007/s10689-017-0061-3

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.