A research brief by Carrot-Zhang et al published in Cancer Discovery investigating inherited lung cancer risk—especially in nonsmokers—in Latin America has found that independent of smoking status, variation in EGFR and KRAS mutation frequency in Latin American patients with lung cancer was associated with Native American ancestry. The findings suggest that one or more genetic loci specific to Native American ancestry may modulate the evolution of lung cancer tumors to harbor EGFR or KRAS mutations in Latin American populations and may provide prevention and early detection strategies for lung cancer in Latin America and in other countries, especially for nonsmokers.

Globally, lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer death, with an estimated 2.1 million lung cancer cases and 1.8 million deaths each year, mostly the result of inadequate tobacco control policies. In the Americas, lung cancer kills more people than any other malignancy, a trend that is expected to continue until 2030, unless tobacco control efforts are increased.

Study Methodology

The researchers performed genomic and ancestry analysis on tissue samples from 1,153 patients with lung cancer from Latin America. Of these patients, 601 were from Mexico and 552 were from Colombia; 499 patients self-reported themselves as nonsmokers.

Researchers used next-generation sequencing targeting a panel of 547 cancer genes, plus intronic regions of 60 cancer genes, to identify single-nucleotide variants, indels, and gene fusions. Because the researchers did not have matched germline samples, they applied a custom script to identify known hotspot lung cancer driver mutations for the full 1,153 samples to ensure the sensitivity for low-coverage samples, as well as to avoid potential germline contamination.

Study Results

The researchers found that 552 (48%) of all samples harbored oncogenic mutations in EGFR, KRAS, BRAF, ERBB2, or MET, or fusions in ALK, ROS1, or RET; 785 of the 1,153 samples harbored at least one detectable alteration in a broader set of known lung cancer driver genes also including TP53, STK11, KEAP1, SMARCA4, SETD2, MYC, and MDM2.

Using a new method of ancestry analysis developed by two investigators on this study—lead author Jian Carrot-Zhang, PhD, a postdoctoral research fellow at Dana-Farber Cancer Institute and Broad Institute, and Alexander Gusev, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School—the researchers also performed ancestry analyses from tumor samples in this admixed population. Global ancestry analysis was performed to measure proportions of African, European, and Native American ancestry across the genome. In addition, local ancestry analysis, which evaluates genetic ancestry at a particular chromosomal location, was performed.

Using the genomic and ancestry data, the researchers assessed the associations of somatic mutations in target genes and global ancestry groups within a single admixed population. After adjusting for a variety of factors, including self-reported smoking status and sample-specific tumor mutational burden, the researchers found that global Native American ancestry was positively correlated with mutations in the EGFR gene. The researchers also found that Native American ancestry was predominantly associated with oncogenic mutations in the EGFR gene, but not with nononcogenic mutations.

The researchers then stratified patients by their self-reported smoking status and evaluated the association between global ancestry and mutations in target genes. They found that in both never-smokers and smokers, global Native American ancestry was associated with mutations in the EGFR gene, suggesting that the genomic differences associated with Native American ancestry are independent of smoking status.

The researchers next developed a local Native American ancestry risk score to evaluate the association of ancestry with EGFR mutation frequency across multiple distinct sites in the genome. They found that the correlation between ancestry and increased mutation frequency in the EGFR gene was stronger at the local genome level than at the global genome level.

Clinical Significance

Matthew Meyerson, MD, PhD

“Smoking increases the risk of KRAS-mutant lung cancers, while patients with lung cancer who are nonsmokers more often develop EGFR-mutant lung cancer,” said Matthew Meyerson, MD, PhD, Director of the Center for Cancer Genomics at Dana-Farber Cancer Institute, Professor of Genetics and Medicine at Dana-Farber Cancer Institute and Harvard Medical School, Institute Member of the Broad Institute of MIT and Harvard, and senior author of this study. “However, we show in our study that EGFR-mutant lung cancer is also elevated among smokers with Native American ancestry. Many lung cancers are now treatable with targeted therapy or immunotherapy. 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.”

Disclosure: Funding for this study was provided by the V Foundation and the National Cancer Institute. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.