Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

Edward J Saunders; Tokhir Dadaev; Daniel A Leongamornlert; Ali Amin Al Olama; Sara Benlloch; Graham G Giles; Fredrik Wiklund; Henrik Gronberg; Christopher A Haiman; Johanna Schleutker; Børge Nordestgaard; Ruth C Travis; David Neal; Nora Pasayan; Kay-Tee Khaw; Janet L Stanford; William J Blot; Stephen N Thibodeau; Christiane Maier; Adam S Kibel; Cezary Cybulski; Lisa Cannon-Albright; Hermann Brenner; Jong Y Park; Radka Kaneva; Jyotsna Batra; Manuel R Teixeira; Hardev Pandha; Koveela Govindasami; Ken Muir; Douglas F Easton; Rosalind A Eeles; Zsofia Kote-Jarai; UK Genetic Prostate Cancer Study Collaborators

doi:10.1038/bjc.2016.50

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

Edward J Saunders, Tokhir Dadaev, Daniel A Leongamornlert, Ali Amin Al Olama, Sara Benlloch, Graham G Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna Schleutker, Børge Nordestgaard, Ruth C Travis, David Neal, Nora Pasayan, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen N Thibodeau, Christiane Maier, Adam S KibelCezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Koveela Govindasami, Ken Muir, Douglas F Easton, Rosalind A Eeles, Zsofia Kote-Jarai, UK Genetic Prostate Cancer Study Collaborators

Department of Clinical Medicine

11 Citations (Scopus)

Abstract

Background:Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods:Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results:Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions:MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Original language	English
Journal	British Journal of Cancer
Volume	114
Pages (from-to)	945-52
Number of pages	8
ISSN	0007-0920
DOIs	https://doi.org/10.1038/bjc.2016.50
Publication status	Published - 12 Apr 2016

Keywords

BRCA1 Protein
Case-Control Studies
Cell Cycle Proteins
DNA
DNA Repair
DNA Repair Enzymes
DNA-Binding Proteins
Genes, BRCA2
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Germ-Line Mutation
Humans
Male
Polymorphism, Single Nucleotide
Prospective Studies
Prostatic Neoplasms
Risk
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Al Olama, A. A., Benlloch, S., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B., Travis, R. C., Neal, D., Pasayan, N., Khaw, K-T., Stanford, J. L., Blot, W. J., Thibodeau, S. N., Maier, C., ... UK Genetic Prostate Cancer Study Collaborators (2016). Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. British Journal of Cancer, 114, 945-52. https://doi.org/10.1038/bjc.2016.50

Saunders, EJ, Dadaev, T, Leongamornlert, DA, Al Olama, AA, Benlloch, S, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, B, Travis, RC, Neal, D, Pasayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, SN, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Govindasami, K, Muir, K, Easton, DF, Eeles, RA, Kote-Jarai, Z & UK Genetic Prostate Cancer Study Collaborators 2016, 'Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array', British Journal of Cancer, vol. 114, pp. 945-52. https://doi.org/10.1038/bjc.2016.50

@article{3f5d29e5a8a9486f9227a8cadf335ea1,

title = "Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array",

abstract = "Background:Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods:Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results:Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions:MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.",

keywords = "BRCA1 Protein, Case-Control Studies, Cell Cycle Proteins, DNA, DNA Repair, DNA Repair Enzymes, DNA-Binding Proteins, Genes, BRCA2, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Humans, Male, Polymorphism, Single Nucleotide, Prospective Studies, Prostatic Neoplasms, Risk, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

author = "Saunders, {Edward J} and Tokhir Dadaev and Leongamornlert, {Daniel A} and {Al Olama}, {Ali Amin} and Sara Benlloch and Giles, {Graham G} and Fredrik Wiklund and Henrik Gronberg and Haiman, {Christopher A} and Johanna Schleutker and B{\o}rge Nordestgaard and Travis, {Ruth C} and David Neal and Nora Pasayan and Kay-Tee Khaw and Stanford, {Janet L} and Blot, {William J} and Thibodeau, {Stephen N} and Christiane Maier and Kibel, {Adam S} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Park, {Jong Y} and Radka Kaneva and Jyotsna Batra and Teixeira, {Manuel R} and Hardev Pandha and Koveela Govindasami and Ken Muir and Easton, {Douglas F} and Eeles, {Rosalind A} and Zsofia Kote-Jarai and {UK Genetic Prostate Cancer Study Collaborators}",

year = "2016",

month = apr,

day = "12",

doi = "10.1038/bjc.2016.50",

language = "English",

volume = "114",

pages = "945--52",

journal = "The British journal of cancer. Supplement",

issn = "0007-0920",

publisher = "nature publishing group",

}

TY - JOUR

T1 - Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

AU - Saunders, Edward J

AU - Dadaev, Tokhir

AU - Leongamornlert, Daniel A

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Giles, Graham G

AU - Wiklund, Fredrik

AU - Gronberg, Henrik

AU - Haiman, Christopher A

AU - Schleutker, Johanna

AU - Nordestgaard, Børge

AU - Travis, Ruth C

AU - Neal, David

AU - Pasayan, Nora

AU - Khaw, Kay-Tee

AU - Stanford, Janet L

AU - Blot, William J

AU - Thibodeau, Stephen N

AU - Maier, Christiane

AU - Kibel, Adam S

AU - Cybulski, Cezary

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Park, Jong Y

AU - Kaneva, Radka

AU - Batra, Jyotsna

AU - Teixeira, Manuel R

AU - Pandha, Hardev

AU - Govindasami, Koveela

AU - Muir, Ken

AU - Easton, Douglas F

AU - Eeles, Rosalind A

AU - Kote-Jarai, Zsofia

AU - UK Genetic Prostate Cancer Study Collaborators

PY - 2016/4/12

Y1 - 2016/4/12

N2 - Background:Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods:Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results:Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions:MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

AB - Background:Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods:Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results:Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions:MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

KW - BRCA1 Protein

KW - Case-Control Studies

KW - Cell Cycle Proteins

KW - DNA

KW - DNA Repair

KW - DNA Repair Enzymes

KW - DNA-Binding Proteins

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Prostatic Neoplasms

KW - Risk

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

UR - https://www.nature.com/articles/bjc2017468

U2 - 10.1038/bjc.2016.50

DO - 10.1038/bjc.2016.50

M3 - Journal article

C2 - 26964030

SN - 0007-0920

VL - 114

SP - 945

EP - 952

JO - The British journal of cancer. Supplement

JF - The British journal of cancer. Supplement

ER -

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

Abstract

Keywords

UN SDGs

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