Abstract
Precision medicine relies on targeting specific somatic alterations present in a patient's tumor. However, the extent to which germline ancestry may influence the somatic burden of disease has received little attention. We estimated the genetic ancestry of non‐small‐cell lung cancer (NSCLC) patients and performed an in‐depth analysis of the influence of genetic ancestry on the evolutionary disease course. Compared with European Americans (EA), African Americans (AA) with lung adenocarcinoma (LUAD) were found to be significantly younger and smoke significantly less. However, LUADs from AAs exhibited a significantly higher somatic mutation burden, with a more pronounced tobacco carcinogen footprint and increased frequencies of alterations affecting cancer genes. Conversely, no significant differences were observed between lung squamous cell carcinomas (LUSC) from EAs and AAs. Our results suggest germline ancestry influences the somatic evolution of LUAD but not LUSC.
Highlights
Large-scale sequencing projects, including the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have revolutionized our understanding of the genomic basis of cancer. Studies building upon these data have identified scores of cancer-associated genes (Bailey et al, 2018; Lawrence et al, 2014) and revealed many of the mutational processes underpinning cancer development (Alexandrov et al, 2015, Alexandrov et al, 2013, Alexandrov et al, 2020)
Women with African ancestry (AA) have been reported to have higher breast cancer mortality, compared to women with European ancestry (EA), which has been associated with a higher occurrence of the more aggressive triple-negative form (Daly & Olopade, 2015)
When we applied the same procedure to CS2, calculating propensity scores considering age and APOBEC3B expression, the significant difference remains (Figure 4) (No clear differences in mutational signatures were observed between AA and EA lung squamous cell carcinomas (LUSC) tumors, Figure S3)
Summary
Large-scale sequencing projects, including the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have revolutionized our understanding of the genomic basis of cancer. Studies building upon these data have identified scores of cancer-associated genes (Bailey et al, 2018; Lawrence et al, 2014) and revealed many of the mutational processes underpinning cancer development (Alexandrov et al, 2015, Alexandrov et al, 2013, Alexandrov et al, 2020). Colorectal cancer has been shown to be more lethal in both AA men and women relative to EA individuals (O'Keefe et al, 2015). We investigate differences in the strength of association between tobacco exposure and lung cancer development
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