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

Lorelei A Mucci, Kathryn L Penney, Chaoran Ma, Xiaoyu Wang, James Y Dai, Constance Turman, Peter Kraft, Konrad H Stopsack, Massimo Loda, Andreas Pettersson, Janet L Stanford

Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2023;32(10):1436-1443

PMID: 37555839

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Abstract

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.

Address: Department of Nutrition, University of Massachusetts Amherst, Amherst, Massachusetts.; Division of Public Health Sciences, Fred Hutchison Cancer Center, Seattle, Washington.; Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington.; 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.; Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.; Weill Cornell Medicine, New York, New York.; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

DOI: 10.1158/1055-9965.EPI-23-0275