A recent study, published by the American Association for Cancer Research has discovered that among patients with lung cancer from Latin America, Native American ancestry is associated with increased mutations in the EGFR gene, independent of smoking status.
Professor Matthew Meyerson, author of this paper and Director of the Centre for Cancer Genomics at the Dana-Farber Cancer institute in Boston, explained that “lung cancer is the leading cause of cancer mortality, both in the US and globally.” Developing an understanding of the inherited risk factors for lung cancer may help to identify populations that would benefit from increased screening efforts.
Previous studies have identified that EGFR-mutant lung cancer is more common in East Asian populations compared to North American or European populations, about 50% vs 10% of lung cancer cases, respectively. However, it is unknown whether this difference is due to environmental or genetic factors.
Meyerson and colleagues analysed samples from 1,153 lung cancer patients from Latin America. 499 of these patients self-reported as non-smokers. Genomic analyses of tumour samples identified somatic mutations in several target genes, including EGFR and KRAS.
The researchers also performed ancestry analyses from the tumour samples of patients. These measured the proportions of African, European and Native American ancestry across the genome. They also completed a local ancestry analysis, which only examines a small segment of the genome, reducing the confounding of data by environmental factors and socioeconomic status.
The Impacts of Native American Ancestry
Using genomic and ancestry data, the researchers measured the correlation between target gene mutations and global ancestry groups. They also adjusted for smoking status and sample-specific tumour mutational burden. It was found that Native American ancestry was positively correlated with mutations in the EGFR gene. This association was also stronger with oncogenic mutations in the EGFR gene than with non-oncogenic mutations.
They then stratified participants by their self-reported smoking status and evaluated the correlation between global ancestry and mutations in target genes. It was found that Native American ancestry was associated with mutations in the EGFR gene in both smokers and never-smokers. These results suggest that the impacts of ancestry are independent of smoking status.
Smoking is known to increase the risk for KRAS-mutant lung cancers. Alternatively, non-smokers who develop lung cancer generally develop EGFR-mutant lung cancer. This study demonstrates that this type of cancer is also elevated among those with Native American ancestry.
Native American Ancestry Risk Scores
The researchers developed a local Native American ancestry risk score. This measured the association of ancestry with EGFR mutation frequency across multiple distinct sites in the genome. Their results found that correlations between ancestry and EGFR-mutations were stronger at the local-genome level than at the global-genome level. These results may suggest that germline genetics, in addition to environmental factors and socioeconomic status, may influence the risk of EGFR-mutant lung cancer among those of Native American ancestry.
The authors acknowledge that their results are limited by a small sample size. This prevented the identification of a specific gene or site within the germline associated with increased EGFR-mutations in these patients. Furthermore, the researchers only tested known hotspot mutations in lung cancer driver genes. Future work will be needed to characterise lung cancer genomes specifically for Latin American patients.