3091 - Genomic Insights into Prostate Cancer Trends in Black/African American Men

Purpose/Objective(s):

Prostate cancer (PCa) incidence in the United States is the highest among Black/African American (BAA) men compared to all other racial groups. Expert panels advocate for PSA screening as early as in the 40s for BAA males. Potential genetic, environmental, socioeconomic, and structural factors that may contribute to PCa disparities have been studied. However, recent data shows that race alone is not associated with worse outcomes when controlling for other-cause mortality and access to standardized care. Data even shows that PCa specific mortality is superior with radiation therapy among BAA compared to White males. We aimed to investigate genomic alterations associated with BAA race.

Materials/Methods:

Primary tumor mutational data was queried from The Cancer Genome Atlas (TCGA) prostate cancer dataset. Each of the 321 FoundationOne CDx panel cancer susceptibility genes was analyzed individually for association with BAA race using univariate logistic regression (UVA), with mutations as predictors and BAA race the outcome. Significant genes were then evaluated in a multivariate logistic regression (MVA) model, adjusting for age, clinical T stage, pathologic T and N stage, and Gleason grade. Loss-of-function (LoF) ATM mutations were defined a priori as frameshift, nonsense, start/stop codon changes, deleterious splice site mutations, missense mutations linked to germline ataxia-telangiectasia, or identified as pathogenic per the NCBI ClinVar database. All statistical analyses were conducted using R and Python 3.7 with the scipy.stats, statsmodels, and sklearn libraries.

Results:

A total of 426 patients were included in the final cohort, of whom 49 (11.5%) were identified as BAA. BAA patients had significantly lower mean age (58.5 vs. 61.7 years, p = 0.002), T stage (31.6% vs. 51.0% T2, p=0.02), and Gleason grade (16.3% vs. 45.3% Gleason 8-10, p<0.001) versus non-BAA patients. ATM was the only gene found to be associated with BAA race on UVA; no ATM mutations in BAA patients were LoF. ATM mutations were identified in 19 out of 426 patients (4.5%) in the overall cohort: 5 of 49 (10.2%) BAA compared to 14 of 377 (3.7%) non-BAA patients. On UVA, ATM mutations were significantly associated with BAA race (Odds Ratio [OR]: 2.95, 95% Confidence Interval [CI]: 1.01–8.57, p = 0.047). This association remained significant on MVA (OR: 5.41, 95% CI: 1.50-17.80, p = 0.006).

Conclusion:

Mutations in the ATM gene were associated with BAA race in the TCGA dataset. Given the association of ATM mutations with both hereditary predisposition to cancer and radiation sensitivity, this is a hypothesis-generating finding with potential implications for PCa prognostication and patient management. It should be validated in a larger dataset and potentially tested prospectively as it has the capacity to inform treatment personalization for BAA men, particularly when considering radiation therapy or prostatectomy.