Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium

Reka Toth, Dominique Scherer, Linda E. Kelemen, Angela Risch, Aditi Hazra, Yesilda Balavarca, Jean Pierre J. Issa, Victor Moreno, Rosalind A. Eeles, Shuji Ogino, Xifeng Wu, Yuanqing Ye, Rayjean J. Hung, Ellen L Goode, Cornelia M. Ulrich

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR=1.14; 95% confidence interval (CI)=1.10-1.19; q = 6.87 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR=1.06; 95% CI=1.03-1.08; q=0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.

Original languageEnglish (US)
Pages (from-to)816-825
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume26
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Epigenomics
Breast
Neoplasms
Estrogen Receptors
Prostate
Confidence Intervals
Ovarian Neoplasms
Prostatic Neoplasms
Genetic Pleiotropy
Genetic Epigenesis
Genes
Lung
Single Nucleotide Polymorphism
Epithelial Cells
Genotype
Carcinoma

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium. / Toth, Reka; Scherer, Dominique; Kelemen, Linda E.; Risch, Angela; Hazra, Aditi; Balavarca, Yesilda; Issa, Jean Pierre J.; Moreno, Victor; Eeles, Rosalind A.; Ogino, Shuji; Wu, Xifeng; Ye, Yuanqing; Hung, Rayjean J.; Goode, Ellen L; Ulrich, Cornelia M.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 26, No. 6, 01.06.2017, p. 816-825.

Research output: Contribution to journalArticle

Toth, R, Scherer, D, Kelemen, LE, Risch, A, Hazra, A, Balavarca, Y, Issa, JPJ, Moreno, V, Eeles, RA, Ogino, S, Wu, X, Ye, Y, Hung, RJ, Goode, EL & Ulrich, CM 2017, 'Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium', Cancer Epidemiology Biomarkers and Prevention, vol. 26, no. 6, pp. 816-825. https://doi.org/10.1158/1055-9965.EPI-16-0728
Toth, Reka ; Scherer, Dominique ; Kelemen, Linda E. ; Risch, Angela ; Hazra, Aditi ; Balavarca, Yesilda ; Issa, Jean Pierre J. ; Moreno, Victor ; Eeles, Rosalind A. ; Ogino, Shuji ; Wu, Xifeng ; Ye, Yuanqing ; Hung, Rayjean J. ; Goode, Ellen L ; Ulrich, Cornelia M. / Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium. In: Cancer Epidemiology Biomarkers and Prevention. 2017 ; Vol. 26, No. 6. pp. 816-825.
@article{3ae197061db347e18e52a0eb318cee84,
title = "Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium",
abstract = "Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR=1.14; 95{\%} confidence interval (CI)=1.10-1.19; q = 6.87 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95{\%} CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR=1.06; 95{\%} CI=1.03-1.08; q=0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.",
author = "Reka Toth and Dominique Scherer and Kelemen, {Linda E.} and Angela Risch and Aditi Hazra and Yesilda Balavarca and Issa, {Jean Pierre J.} and Victor Moreno and Eeles, {Rosalind A.} and Shuji Ogino and Xifeng Wu and Yuanqing Ye and Hung, {Rayjean J.} and Goode, {Ellen L} and Ulrich, {Cornelia M.}",
year = "2017",
month = "6",
day = "1",
doi = "10.1158/1055-9965.EPI-16-0728",
language = "English (US)",
volume = "26",
pages = "816--825",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Genetic variants in epigenetic pathways and risks of multiple cancers in the game-on consortium

AU - Toth, Reka

AU - Scherer, Dominique

AU - Kelemen, Linda E.

AU - Risch, Angela

AU - Hazra, Aditi

AU - Balavarca, Yesilda

AU - Issa, Jean Pierre J.

AU - Moreno, Victor

AU - Eeles, Rosalind A.

AU - Ogino, Shuji

AU - Wu, Xifeng

AU - Ye, Yuanqing

AU - Hung, Rayjean J.

AU - Goode, Ellen L

AU - Ulrich, Cornelia M.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR=1.14; 95% confidence interval (CI)=1.10-1.19; q = 6.87 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR=1.06; 95% CI=1.03-1.08; q=0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.

AB - Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR=1.14; 95% confidence interval (CI)=1.10-1.19; q = 6.87 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR=1.06; 95% CI=1.03-1.08; q=0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.

UR - http://www.scopus.com/inward/record.url?scp=85019613861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019613861&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-16-0728

DO - 10.1158/1055-9965.EPI-16-0728

M3 - Article

C2 - 28115406

AN - SCOPUS:85019613861

VL - 26

SP - 816

EP - 825

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 6

ER -