Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Division of Intramural Research, National Institute on Minority Health and Health Disparities, Bethesda, Maryland; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
J Thorac Oncol. 2020 Dec;15(12):1880-1892. doi: 10.1016/j.jtho.2020.08.029. Epub 2020 Sep 12.
Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States, especially among men. Although significant progress has been made profiling the genomic makeup of lung cancer in EAs, AAs continue to be underrepresented. Our objective was to chart the genome-wide landscape of somatic mutations in lung cancer tumors from AAs.
In this study, we used the whole-exome sequencing of 82 tumor and noninvolved tissue pairs from AAs. Patients were selected from an ongoing case-control study conducted by the National Cancer Institute and the University of Maryland.
Among all samples, we identified 178 significantly mutated genes (p < 0.05), five of which passed the threshold for false discovery rate (p < 0.1). In lung adenocarcinoma (LUAD) tumors, mutation rates in STK11 (p = 0.05) and RB1 (p = 0.008) were significantly higher in AA LUAD tumors (25% and 13%, respectively) compared with The Cancer Genome Atlas EA samples (14% and 4%, respectively). In squamous cell carcinomas, mutation rates in STK11 (p = 0.002) were significantly higher among AA (8%) than EA tumors from The Cancer Genome Atlas (1%). Integrated somatic mutation data with CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) data analysis revealed LUAD tumors from AAs carrying STK11 mutations have decreased interferon signaling.
Although a considerable degree of the somatic mutation landscape is shared between EAs and AAs, discrete differences in mutation frequency in potentially important oncogenes and tumor suppressors exist. A better understanding of the molecular basis of lung cancer in AA patients and leveraging this information to guide clinical interventions may help reduce disparities.
在美国，非裔美国人（AA）的肺癌发病率高于欧洲裔美国人（EA），尤其是男性。尽管在 EA 肺癌的基因组特征方面已经取得了显著进展，但 AA 仍然代表性不足。我们的目标是描绘 AA 肺癌肿瘤全基因组体细胞突变的全景。
在这项研究中，我们使用了 82 对 AA 的肿瘤和未受影响组织的全外显子组测序。这些患者是从美国国立癌症研究所和马里兰大学进行的一项正在进行的病例对照研究中选择的。
在所有样本中，我们鉴定出 178 个显著突变基因（p < 0.05），其中 5 个通过了假发现率（p < 0.1）的阈值。在肺腺癌（LUAD）肿瘤中，STK11（p = 0.05）和 RB1（p = 0.008）的突变率在 AA LUAD 肿瘤中明显更高（分别为 25%和 13%），而在 TCGA 的 EA 样本中分别为 14%和 4%。在鳞状细胞癌中，STK11 的突变率在 AA（8%）中明显高于 TCGA 的 EA 肿瘤（1%）（p = 0.002）。整合体细胞突变数据与 CIBERSORT（通过估计相对 RNA 转录物子集来鉴定细胞类型）数据分析显示，携带 STK11 突变的 AA LUAD 肿瘤中干扰素信号减弱。
尽管 EA 和 AA 之间存在相当程度的体细胞突变景观共享，但在潜在重要的致癌基因和肿瘤抑制基因的突变频率上存在离散差异。更好地了解 AA 患者肺癌的分子基础，并利用这些信息指导临床干预，可能有助于减少差异。
