Germline Genetic Variants Associated with Somatic TMPRSS2:ERG Fusion Status in Prostate Cancer: A Genome-Wide Association Study.

Male Humans Genome-Wide Association Study Follow-Up Studies Oncogene Proteins, Fusion / genetics Prostatic Neoplasms / genetics Germ-Line Mutation Transcriptional Regulator ERG / genetics Serine Endopeptidases / genetics

Journal

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
ISSN: 1538-7755
Titre abrégé: Cancer Epidemiol Biomarkers Prev
Pays: United States
ID NLM: 9200608

Informations de publication

Date de publication:
02 10 2023
Historique:
received: 22 03 2023
revised: 12 05 2023
accepted: 04 08 2023
pmc-release: 02 04 2024
medline: 23 10 2023
pubmed: 9 8 2023
entrez: 9 8 2023
Statut: ppublish

Résumé

The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status. We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification. We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance. We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion. Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.

Sections du résumé

BACKGROUND
The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status.
METHODS
We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification.
RESULTS
We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance.
CONCLUSIONS
We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion.
IMPACT
Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.

Identifiants

DOI: 10.1158/1055-9965.EPI-23-0275 PMID: 37555839 PMC: PMC10592169
pubmed: 37555839
pii: 728393
doi: 10.1158/1055-9965.EPI-23-0275
pmc: PMC10592169
mid: NIHMS1925328
doi:

Substances chimiques

Oncogene Proteins, Fusion 0
Transcriptional Regulator ERG 0
ERG protein, human 0
TMPRSS2 protein, human EC 3.4.21.-
Serine Endopeptidases EC 3.4.21.-

Types de publication

Meta-Analysis Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1436-1443

Subventions

Organisme : NCI NIH HHS
ID : U10 CA037429
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA188392
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA128978
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148537
Pays : United States
Organisme : NCI NIH HHS
ID : K05 CA175147
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA098233
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148112
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA098758
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA092579
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA098710
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167552
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222833
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA098216
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA056678
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008C
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA182883
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States

Informations de copyright

©2023 American Association for Cancer Research.

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Auteurs

Chaoran Ma (C)

Department of Nutrition, University of Massachusetts Amherst, Amherst, Massachusetts.
ORCID: 0000-0003-3683-3218

Xiaoyu Wang (X)

Division of Public Health Sciences, Fred Hutchison Cancer Center, Seattle, Washington.
ORCID: 0000-0002-4504-7799

James Y Dai (JY)

Division of Public Health Sciences, Fred Hutchison Cancer Center, Seattle, Washington.
Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington.
ORCID: 0000-0001-6479-9286

Constance Turman (C)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
ORCID: 0000-0002-7790-8311

Peter Kraft (P)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
ORCID: 0000-0002-4472-8103

Konrad H Stopsack (KH)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
ORCID: 0000-0002-0722-1311

Massimo Loda (M)

Weill Cornell Medicine, New York, New York.
ORCID: 0000-0001-9674-8379

Andreas Pettersson (A)

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
ORCID: 0000-0003-3316-045X

Lorelei A Mucci (LA)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
ORCID: 0000-0002-2551-4927

Janet L Stanford (JL)

Division of Public Health Sciences, Fred Hutchison Cancer Center, Seattle, Washington.
Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
ORCID: 0000-0001-5062-4784

Kathryn L Penney (KL)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
ORCID: 0000-0002-2815-3450

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