To improve our understanding of longstanding disparities in incidence and mortality in lung cancer across ancestry, we performed a systematic comparative analysis of molecular features in tumors from African Americans (AAs) and European Americans (EAs). We find that lung squamous cell carcinoma tumors from AAs exhibit higher genomic instability—the proportion of non-diploid genome—aggressive molecular features such as chromothripsis and higher homologous recombination deficiency (HRD). In The Cancer Genome Atlas, we demonstrate that high genomic instability, HRD and chromothripsis among tumors from AAs is found across many cancer types. The prevalence of germline HRD (that is, the total number of pathogenic variants in homologous recombination genes) is higher in tumors from AAs, suggesting that the somatic differences observed have genetic ancestry origins. We also identify AA-specific copy-number-based arm-, focal- and gene-level recurrent features in lung cancer, including higher frequencies of PTEN deletion and KRAS amplification. These results highlight the importance of including under-represented populations in genomics research.

为了更好地了解不同血统的肺癌发病率和死亡率的长期差异，我们对非洲裔美国人 (AAs) 和欧洲裔美国人 (EAs) 的肿瘤分子特征进行了系统比较分析。我们发现来自 AA 的肺鳞状细胞癌肿瘤表现出更高的基因组不稳定性——非二倍体基因组的比例——侵袭性分子特征，如染色体碎裂和更高的同源重组缺陷 (HRD)。在癌症基因组图谱中，我们证明了在许多癌症类型中发现来自 AA 的肿瘤中的高基因组不稳定性、HRD 和染色体碎裂。在来自 AA 的肿瘤中，生殖系 HRD（即同源重组基因中致病变异的总数）的患病率较高，表明观察到的体细胞差异具有遗传血统起源。我们还确定了肺癌中基于 AA 特异性拷贝数的臂、局灶和基因水平的复发特征，包括更高频率的PTEN缺失和KRAS扩增。这些结果强调了在基因组学研究中纳入代表性不足的人群的重要性。