<i>CDKN1B</i> Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer.

Abstract

The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis. At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non-organ confined. The median PGA was 3.7% (IQR = 0.9%-9.4%) and differed by pathologic grade (<i>P</i> < 0.001) and stage (<i>P</i> = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55-70.86; <i>P</i> = 0.002). The most common somatic mutations were <i>SPOP</i> (11.2%), <i>FOXA1</i> (8.3%), and <i>TP53</i> (3.9%). The most common loci altered at the copy number level were <i>CDKN1B</i> (6.3%), <i>CHD1</i> (4.4%), and <i>PTEN</i> (3.4%). <i>TP53</i> mutations and deep deletions in <i>CDKN1B</i> were associated with increased risks of metastasis on multivariable analyses (<i>TP53</i>: HR = 9.5; 95% CI, 2.2-40.6; <i>P</i> = 0.002; <i>CDKN1B</i>: HR = 6.7; 95% CI, 1.3-35.2; <i>P</i> = 0.026). Overall, PGA, somatic <i>TP53</i> mutations, and a novel finding of deep deletions in <i>CDKN1B</i> were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.