We aim to understand, from acquired genetic alterations in tumors, why African American (AA) men are more likely to develop aggressive prostate cancer. By analyzing somatic mutations in 39 genes using deeper next-generation sequencing with an average depth of 2,522 reads for tumor DNA and genome-wide DNA copy-number alterations (CNA) in prostate cancer in a total of 171 AA/black men and comparing with those in 860 European American (EA)/white men, we here present several novel findings. First, >35% of AA men harbor damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with >1% of mutated copies. Second, among genes with >10% of mutated copies in tumor cells, ZMYM3 is the most frequently mutated gene in AA prostate cancer. In a patient's tumor with >96% frameshift mutations of ZMYM3, we find allelic imbalances in 10 chromosomes, including losses of five and gains of another four chromosomes, suggesting its role in maintaining genomic integrity. Third, when compared to prostate cancer in EA/white men, a higher frequency of CNAs of MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L and RB1, and a lower frequency of deletions of RYBP, TP53, and TMPRSS2-ERG are observed in AA/black men. Finally, for the above genes with higher frequency of CNAs in AA than in EA, deletion of MAP3K7, BNIP3L, NEIL3 or RB1, or gain of MYC significantly associates with both higher Gleason grade and advanced pathologic stage in AA/black men. Deletion of THADA associates with advanced pathologic stage only. Implications: A higher frequency of damaging mutation in ZMYM3 causing genomic instability along with higher frequency of altered genomic regions including deletions of MAP3K7, BNIP3L, RB1, and NEIL3, and gain of MYC appear to be distinct somatically acquired genetic alterations that may contribute to more aggressive prostate cancer in AA/black men.

中文翻译：

---

源自非裔美国男性的前列腺肿瘤的不同基因组改变

我们的目标是从肿瘤的获得性基因改变中了解为什么非裔美国人 (AA) 男性更容易患上侵袭性前列腺癌。通过使用更深入的下一代测序分析 39 个基因中的体细胞突变，平均深度为 2,522 次读取的肿瘤 DNA 和全基因组 DNA 拷贝数改变 (CNA) 在总共 171 名 AA/黑人男性中进行，并与在 860 名欧洲裔美国人 (EA)/白人男性中，我们在此展示了几个新发现。首先，> 35% 的 AA 男性在 APC、ATM、BRCA2、KDM6A、KMT2C、KMT2D、MED12、ZFHX3 和 ZMYM3 中存在破坏性突变，每个都有 >1% 的突变拷贝。其次，在肿瘤细胞中突变拷贝数大于 10% 的基因中，ZMYM3 是 AA 前列腺癌中最常见的突变基因。在 ZMYM3 移码突变 > 96% 的患者肿瘤中，我们发现 10 条染色体的等位基因不平衡，包括 5 条染色体丢失和另外 4 条染色体增加，表明其在维持基因组完整性方面的作用。第三，与 EA/白人男性的前列腺癌相比，MYC、THADA、NEIL3、LRP1B、BUB1B、MAP3K7、BNIP3L 和 RB1 的 CNA 频率更高，而 RYBP、TP53 和 TMPRSS2-ERG 的缺失频率更低在 AA/黑人男性中观察到。最后，对于上述 AA 中 CNA 频率高于 EA 的基因，MAP3K7、BNIP3L、NEIL3 或 RB1 的缺失或 MYC 的增加与 AA/黑人男性的较高 Gleason 分级和晚期病理分期显着相关。删除 THADA 仅与晚期病理分期有关。含义：