Latin American Patients with Lung Cancer and Native American Ancestry See Increased EGFR Mutations

Genomic and ancestry analyses published in Cancer Discovery revealed that among patients with lung cancer from Latin America, Native American ancestry was associated with increased mutations in the EGFR gene, independent of smoking status.¹

Researchers indicated that these findings suggest that germline genetics, rather than environmental disparities, underlie these observed disparities.

“Lung cancer is the leading cause of cancer mortality, both in the United States and globally, and understanding inherited risk factors for this disease may help us to identify populations that would benefit from increased screening efforts,” Matthew Meyerson, MD, PhD, director of the Center for Cancer Genomics at Dana-Farber Cancer Institute in Boston, said in a press release.²

To explore the landscape of somatic cancer mutation in lung cancers from Latin America and to evaluate the influence of germline ancestry of genetically amalgamated patient populations on these somatic alterations, the study investigators performed genomic analysis of 601 lung cancer cases from Mexico and 552 from Colombia, including 499 self-reported non-smokers. Next-generation sequencing targeting a panel of 547 cancer genes plus intronic regions of 60 cancer genes was used to identify single nucleotide variants (SNVs), indels, somatic copy number alterations (SCNAs), and gene fusions; importantly, this gene panel covered all currently known lung cancer drivers.

It was discovered that 48% of all samples harbored oncogenic mutations in EGFR, KRAS, BRAF, ERBB2, or MET, or fusions in ALK, ROS1, or RET. Moreover, 785 of 1153 samples harbored at least 1 detectable alteration in a broader set of known lung cancer driver genes also including TP53, STK11, KEAP1, SMARCA4, SETD2, MYC, and MDM2. The detected mutation frequencies of EGFR and KRAS were 30% and 10%, respectively, in the tested lung cancer samples from Mexican patients, and 23% and 13%, respectively, in the tested lung cancer samples from Colombian patients.

Using a new method developed by Jian Carrot-Zhang, PhD, and Alexander Gusev, PhD, ancestry analyses from the tumor samples was also performed in this admixed population of patients. Further, global ancestry analysis was performed to measure proportions of African, European, and Native American ancestry across the genome. In addition, local ancestry analysis was performed, which evaluates genetic ancestry at a particular chromosomal location.

After obtaining data on both somatic alteration and genetic ancestry, the next step for the researchers was assessing the correlation of these features. After adjusting for various factors, including self-reported smoking status and sample-specific tumor mutational burden, it was discovered that global Native American ancestry was positively correlated with mutations in the EGFR gene. Even further, the researchers determined that Native American ancestry was predominantly associated with oncogenic mutations in the EGFR gene, but not with non-oncogenic mutations.

Patients were then stratified by their self-reported smoking status and evaluated to determine the association between global ancestry and mutations in target genes. In both individuals who were never smokers and smokers, global Native American ancestry was found to be associated with mutations in the EGFR gene, indicating that the genomic differences associated with Native American ancestry are independent of smoking status.

“Smoking increases the risk for KRAS-mutant lung cancers, while patients with lung cancer who are non-smokers more often develop EGFR-mutant lung cancer,” Meyerson explained. “However, we show in our study that EGFR-mutant lung cancer is also elevated among smokers with Native American ancestry.”

Lastly, the investigators developed a local Native American ancestry risk score to assess the association of ancestry with EGFR mutation frequency across multiple distinct sites in the genome. In doing so, it was revealed that the correlation between ancestry and increased mutation frequency in the EGFR gene was stronger at the local genome level than the global genome level.

“These results suggest that germline genetics – in addition to environmental factors or socioeconomic status – may have an influence on the risk of EGFR-mutant lung cancer among those with Native American ancestry,” said Meyerson.

“Many lung cancers are now treatable with targeted therapy or immunotherapy,” Meyerson added. “It is very important for patients with lung cancer to undergo somatic genetic testing to determine which treatments are most likely to be effective for their particular cancer.

Moving forward, the researchers suggested that future studies will still be necessary to comprehensively characterize lung cancer genomes from Latin American patients.

References:

1. Carrot-Zhang J, Soca-Chafre G, Patterson N, et al. Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations. Cancer Discovery. doi: 10.1158/2159-8290.CD-20-1165

2. Native American Ancestry Associated With Increased Mutations in EGFR Gene Among Latin American Patients With Lung Cancer [news release]. Philadelphia. Published December 2, 2020. Accessed December 4, 2020.