SNP association study in PMS2-associated Lynch syndrome

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

doi:10.1007/s10689-017-0061-3

SNP association study in PMS2-associated Lynch syndrome

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 WezelMaartje Nielsen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	507-515
Number of pages	9
Journal	Familial Cancer
Volume	17
Issue number	4
DOIs	https://doi.org/10.1007/s10689-017-0061-3
Publication status	Published - 1 Oct 2018

Keywords

Lynch syndrome
PMS2
SNP
Cancer risk
Colorectal cancer
Modifiers
COLORECTAL-CANCER RISK
BODY-MASS INDEX
MUTATION CARRIERS
PMS2 MUTATIONS
VARIANTS
GENES
11Q23.1
COHORT
8Q23.3
MLH1

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Cite this

ten Broeke, S. W., Elsayed, F. A., Pagan, L., Olderode-Berends, M. J. W., Garcia, E. G., Gille, H. J. P., van Hest, L. P., Letteboer, T. G. W., van der Kolk, L. E., Mensenkamp, A. R., van Os, T. A., Spruijt, L., Redeker, B. J. W., Suerink, M., Vos, Y. J., Wagner, A., Wijnen, J. T., Steyerberg, E. W., Tops, C. M. J., ... Nielsen, M. (2018). SNP association study in PMS2-associated Lynch syndrome. Familial Cancer, 17(4), 507-515. https://doi.org/10.1007/s10689-017-0061-3

@article{5865e696f3384a2d8fb2aedad387042e,

title = "SNP association study in PMS2-associated Lynch syndrome",

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 = "Lynch syndrome, PMS2, SNP, Cancer risk, Colorectal cancer, Modifiers, COLORECTAL-CANCER RISK, BODY-MASS INDEX, MUTATION CARRIERS, PMS2 MUTATIONS, VARIANTS, GENES, 11Q23.1, COHORT, 8Q23.3, MLH1",

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

year = "2018",

month = oct,

day = "1",

doi = "10.1007/s10689-017-0061-3",

language = "English",

volume = "17",

pages = "507--515",

journal = "Familial Cancer",

issn = "1389-9600",

publisher = "Springer, Cham",

number = "4",

}

ten Broeke, SW, Elsayed, FA, Pagan, L, Olderode-Berends, MJW, Garcia, EG, Gille, HJP, van Hest, LP, Letteboer, TGW, van der Kolk, LE, Mensenkamp, AR, van Os, TA, Spruijt, L, Redeker, BJW, Suerink, M, Vos, YJ, Wagner, A, Wijnen, JT, Steyerberg, EW, Tops, CMJ, van Wezel, T & Nielsen, M 2018, 'SNP association study in PMS2-associated Lynch syndrome', Familial Cancer, vol. 17, no. 4, pp. 507-515. https://doi.org/10.1007/s10689-017-0061-3

TY - JOUR

T1 - SNP association study in PMS2-associated Lynch syndrome

AU - ten Broeke, Sanne W.

AU - Elsayed, Fadwa A.

AU - Pagan, Lisa

AU - Olderode-Berends, Maran J. W.

AU - Garcia, Encarna Gomez

AU - Gille, Hans J. P.

AU - van Hest, Liselot P.

AU - Letteboer, Tom G. W.

AU - van der Kolk, Lizet E.

AU - Mensenkamp, Arjen R.

AU - van Os, Theo A.

AU - Spruijt, Liesbeth

AU - Redeker, Bert J. W.

AU - Suerink, Manon

AU - Vos, Yvonne J.

AU - Wagner, Anja

AU - Wijnen, Juul T.

AU - Steyerberg, E. W.

AU - Tops, Carli M. J.

AU - van Wezel, Tom

AU - Nielsen, Maartje

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - Lynch syndrome

KW - PMS2

KW - SNP

KW - Cancer risk

KW - Colorectal cancer

KW - Modifiers

KW - COLORECTAL-CANCER RISK

KW - BODY-MASS INDEX

KW - MUTATION CARRIERS

KW - PMS2 MUTATIONS

KW - VARIANTS

KW - GENES

KW - 11Q23.1

KW - COHORT

KW - 8Q23.3

KW - MLH1

U2 - 10.1007/s10689-017-0061-3

DO - 10.1007/s10689-017-0061-3

M3 - Article

C2 - 29147930

SN - 1389-9600

VL - 17

SP - 507

EP - 515

JO - Familial Cancer

JF - Familial Cancer

IS - 4

ER -