. 2023 Feb 8;115(2):190-199.

doi: 10.1093/jnci/djac199.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

Meghana S Pagadala^{1

2

3}, Julie Lynch^{4

5}, Roshan Karunamuni⁶, Patrick R Alba^{4

5}, Kyung Min Lee^{4

5}, Fatai Y Agiri⁴, Tori Anglin^{4

5}, Hannah Carter⁷, J Michael Gaziano^{8

9}, Guneet Kaur Jasuja^{10

11}, Rishi Deka^{1

6

12}, Brent S Rose^{1

6

11}, Matthew S Panizzon^{1

13}, Richard L Hauger^{1

13

14}, Tyler M Seibert^{1

6

15

16}

Affiliations

¹ Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
² Medical Scientist Training Program, University of California San Diego, La Jolla, CA, USA.
³ Biomedical Science Program, University of California San Diego, La Jolla, CA, USA.
⁴ VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System (VINCI), Salt Lake City, UT, USA.
⁵ Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Center for Healthcare Organization and Implementation Research (CHOIR), VA Bedford Healthcare System, Bedford, MA, USA.
¹¹ Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Urology, University of California San Diego, La Jolla, CA, USA.
¹² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹³ Center for Behavioral Genetics of Aging, University of California San Diego, La Jolla, CA, USA.
¹⁴ Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA.
¹⁵ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
¹⁶ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.

PMID: 36305680
PMCID: PMC9905969
DOI: 10.1093/jnci/djac199

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

Meghana S Pagadala et al. J Natl Cancer Inst. 2023.

. 2023 Feb 8;115(2):190-199.

doi: 10.1093/jnci/djac199.

Authors

Affiliations

¹ Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
² Medical Scientist Training Program, University of California San Diego, La Jolla, CA, USA.
³ Biomedical Science Program, University of California San Diego, La Jolla, CA, USA.
⁴ VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System (VINCI), Salt Lake City, UT, USA.
⁵ Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Center for Healthcare Organization and Implementation Research (CHOIR), VA Bedford Healthcare System, Bedford, MA, USA.
¹¹ Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Urology, University of California San Diego, La Jolla, CA, USA.
¹² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹³ Center for Behavioral Genetics of Aging, University of California San Diego, La Jolla, CA, USA.
¹⁴ Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA.
¹⁵ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
¹⁶ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.

PMID: 36305680
PMCID: PMC9905969
DOI: 10.1093/jnci/djac199

Abstract

Background: Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.

Methods: This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.

Results: A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer.

Conclusions: PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

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Figures

**Figure 1.**
Polygenic hazard score based on 290 common variants (PHS290) score density plots in Million Veteran Program. PHS290 score density plot in select self-reported race and ethnicity groups.

**Figure 2.**
Million Veteran Program (MVP) cause-specific cumulative incidence. Cause-specific cumulative incidence within MVP, stratified by polygenic hazard score based on 290 common variants (PHS290), for (A) fatal prostate cancer, (B) metastatic prostate cancer, and (C) prostate cancer. PHS290 percentile groups shown for each endpoint: 0-20th, 30-70th, 80-100th, and 95-100th. Cumulative incidence for Black or African American (Black/AA) men in several PHS290 strata compared with average-risk Non-Hispanic White (PHS290 30-70th percentiles) for (D) fatal prostate cancer, (E) metastatic prostate cancer, and (F) prostate cancer. The y-axis scale was adjusted for (C) and (E) to show the higher incidence values for any prostate cancer.

**Figure 3.**
Million Veteran Program (MVP) cause-specific cumulative incidence using MVP-specific and reference threshold. Cause-specific cumulative incidence for Black or African American (Black/AA) men compared with average-risk Non-Hispanic White (PHS290 30-70th percentiles) stratified by PHS290, for (**A, D**) fatal prostate cancer, (**B, E**) metastatic prostate cancer, and (**C, F**) prostate cancer. PHS290 percentile groups shown for each endpoint: 0-20th, 30-70th, 80-100th, and 95-100th. Incidence curves using MVP group-specific thresholds defined in MVP are shown in **dashed lines**, while reference thresholds are **solid lines**. For example, the purple solid line represents the 5% of Black men with PHS290 below the 20th percentile defined previously in an independent dataset of men with European ancestry. The purple dotted line represents the 20% of Black MVP participants with lowest PHS290 in the present MVP dataset.

See this image and copyright information in PMC

Comment in

RE: Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.
Haiman CA, Kote-Jarai Z, Darst BF, Conti DV. Haiman CA, et al. J Natl Cancer Inst. 2023 Mar 9;115(3):341-342. doi: 10.1093/jnci/djad005. J Natl Cancer Inst. 2023. PMID: 36629487 Free PMC article. No abstract available.

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Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

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Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

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