Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.
Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.
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DOI：
10.1158/1078-0432.ccr-20-2925
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发表时间：
2021-01-01
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影响因子：
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通讯作者：
Yamoah K
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作者：
Awasthi S;Berglund A;Abraham-Miranda J;Rounbehler RJ;Kensler K;Serna A;Vidal A;You S;Freeman MR;Davicioni E;Liu Y;Karnes RJ;Klein EA;Den RB;Trock BJ;Campbell JD;Einstein DJ;Gupta R;Balk S;Lal P;Park JY;Cleveland JL;Rebbeck TR;Freedland SJ;Yamoah K
种族差异在前列腺癌中的免疫肿瘤学机制的作用仍未得到充分研究。有限的研究存在，以评估非洲裔美国人（AAM）和欧洲裔美国人（EAM）前列腺肿瘤微环境（TME）的免疫差异的分子基础。使用了来自Decipher GRID登记处的总共1，173个具有全转录组数据的未经放射治疗的根治性乳腺癌切除术样本。选择1，260个免疫特异性基因的转录组表达来评估AAM和EAM前列腺肿瘤之间的免疫肿瘤学差异。采用秩和检验分析了基因的种族特异性差异表达，并采用基因间相关矩阵和基因集富集进行了途径分析。AAM前列腺肿瘤具有显著富集的主要免疫肿瘤学途径，包括促炎细胞因子、IFNα、IFNγ、TNFα信号传导、IL和上皮-间质转化。AAM TME的总免疫含量评分（ICSHIGH）高于0（37.8% vs. 21.9%，P = 0.003）。与EAM相比，AAM肿瘤还具有较低的DNA损伤修复，并且在基因组上是放射敏感的。IFITM3 IFN-诱导跨膜蛋白3是AAM中过表达的主要促炎基因之一，在发现[HRAAM = 2.30; 95%置信区间（CI），1.21-4.34; P = 0.01]和验证中，该基因选择性预测AAM生化复发风险增加。（HRAAM = 2.42; 95%CI，1.52-3.86; P=0.0001），但在EAM中没有。AAM的前列腺肿瘤表现出独特的免疫库，并且具有与较差结果相关的促炎性免疫途径的显著富集。观察到的免疫肿瘤学差异可以帮助采用基因组适应性方法治疗AAM中的前列腺癌。
The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial–mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21–4.34; P = 0.01] and validation (HRAAM = 2.42; 95%CI, 1.52–3.86; P=0.0001) but not in EAM. Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.