Prostate cancer mortality associated with aggregate polymorphisms in androgen-regulating genes: The atherosclerosis risk in the communities (aric) study

Anna E. Prizment, Sean McSweeney, Nathan Pankratz, Corinne E. Joshu, Justin H. Hwang, Elizabeth A. Platz, Charles J. Ryan

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.

Original languageEnglish (US)
Article number1958
JournalCancers
Volume13
Issue number8
DOIs
StatePublished - Apr 19 2021

Bibliographical note

Funding Information:
This research has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, HHSN268201700002I). Studies on cancer in ARIC are also supported by the National Cancer Institute U01CA164975. Dr. Platz was supported by P30 CA006973. The authors thank the staff and participants of the ARIC study for their important contributions. Cancer incidence data have been provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD21201, USA. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC) for the funds that helped support the availability of the cancer registry data.

Funding Information:
Acknowledgments: The authors thank the staff and participants of the ARIC study for their important contributions. Cancer incidence data have been provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD21201, USA. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC) for the funds that helped support the availability of the cancer registry data.

Funding Information:
Funding: This research has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, HHSN268201700002I). Studies on cancer in ARIC are also supported by the National Cancer Institute U01CA164975. Dr. Platz was supported by P30 CA006973.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Androgen
  • Androgen-regulating genes
  • Genetic polymorphisms
  • Genetic risk score
  • Prostate cancer
  • Survival

PubMed: MeSH publication types

  • Journal Article

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