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.

中文翻译：

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CDKN1B 缺失与非裔美国男性临床局部、手术治疗的前列腺癌的转移有关。

目的：非裔美国人 (AA) 男性侵袭性前列腺癌的潜在生物学决定因素尚不清楚。在这里，我们描述了迄今为止最大的 AA 男性队列中前列腺癌基因组改变的特征，这些患者对转移进行了临床随访，目的是阐明与该人群预后不良相关的关键分子驱动因素。实验设计：对来自接受根治性前列腺切除术 (RP) 治疗的 AA 男性的 205 个前列腺肿瘤进行回顾性靶向测序，以检查体细胞基因组改变和具有拷贝数改变 (PGA) 的基因组百分比。Cox 比例风险分析评估了基因组改变与转移风险的关联。结果：在 RP 时，71% (145/205) 的患者具有分级组≥3 的疾病，49% (99/202) 为非器官受限。中位 PGA 为 3.7%（IQR = 0. 9%–9.4%），并因病理分级（ P < 0.001）和分期（ P = 0.02）而异。中位随访时间为 5 年。PGA 最高四分位数的 AA 男性转移风险增加（多变量：HR = 13.45；95% CI，2.55–70.86；P = 0.002）。最常见的体细胞突变是 SPOP (11.2%)、FOXA1 (8.3%) 和 TP53 (3.9%)。在拷贝数水平上改变的最常见基因座是 CDKN1B (6.3%)、CHD1 (4.4%) 和 PTEN (3.4%)。在多变量分析中，CDKN1B 中的 TP53 突变和深度缺失与转移风险增加相关（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）。结论：总体而言，PGA、体细胞 TP53 突变和 CDKN1B 深度缺失的新发现与 AA 男性的不良预后相关。这些发现需要在其他 AA 队列中得到证实。