CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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 (P < 0.001) and stage (P = 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; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2-40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3-35.2; P = 0.026).

Conclusions: Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.

Figure 1.. Correlation of clinical outcomes and genomic alterations in African American cohort.

(A) Kaplan-Meier plot of metastasis-free survival by quartile of percent genome alteration. (B) Oncoprint showing distribution of somatic mutations and copy number alterations for AA cohort. (C) Kaplan-Meier plot of metastasis-free survival by presence of TP53 mutation compared to wild type. (D) Kaplan-Meier plot of metastasis-free survival by presence of CDKN1B deep deletions compared to wild type.

Figure 2.. p27 immunostaining in African-American prostate tumors with CDKN1B deep deletions.

Both cases showed deep deletions of CDKN1B by sequencing, however the tumor on the left demonstrates homogeneous loss of p27 protein, suggestive of a clonal alteration, while the tumor on the right shows heterogeneous loss of p27 in some (arrow) but not all (arrowhead) tumor cells, suggestive of a subclonal alteration in CDKN1B. In both cases, benign glands (B) provide an internal positive control for p27 staining. All images reduced from 200x magnification.