Native American Ancestry Correlates With EGFR, KRAS Mutations in Lung Cancer

Jian Carrot-Zhang, MD

An association has been found in Latin American patients with lung adenocarcinoma between Native American ancestry and somatic landscape, including EGFR, KRAS, and STK11 mutations, as well as tumor mutational burden (TMB), according to the results of a genomic and ancestry analysis.¹

A positive correlation was observed between Native American ancestry and EGFR mutations (FDR corrected P = 9 x 10-5; coefficient [coef.] = .005), as well as an anti-correlation with KRAS (FDR corrected P = 9 x 10-5; coef. = -.007) and STK11 mutations (FDR corrected P = 7 x 10-4; coef. = -.013). Each aberration, including TMB, as well as EGFR, KRAS, and STK11 mutations, was found to be independently associated with Native American ancestry in a joint model.

TMB and Native American ancestry had a stronger association in EGFR-mutant never-smokers (P = .002; coef. = -.031) compared with EGFR wild-type never-smokers (P = .038; coef. = -.013). Additionally, interactions between Native American ancestry and EGFR were found to have a significant association with TMB (P = .04; coef. = -.022). This could suggest that the association observed between TMB and Native American Ancestry is different between EGFR-mutant and wild-type samples.

“Our study shows that while controlling for global ancestry, local ancestry is associated with mutations in EGFR and KRAS, providing the first example, to our knowledge, of a germline influence, which may or may not act together with ancestry-specific environmental exposure, on targetable somatic events in lung cancer. These findings highlight the importance of providing somatic genetic testing for Latin American lung cancer patients with admixed ancestries,” Jian Carrot-Zhang, MD, instructor in medicine at Harvard Medical School, and coinvestigators wrote in the study.

While Native American ancestry additionally demonstrated a predominant association with oncogenic driver mutations in EGFR, it did not demonstrate an association with non-oncogenic, passenger mutations. Investigators did not note somatic copy-number alterations (SCNAs) of any lung cancer driver genes that were associated with ancestry.

Investigators notably found an anti-correlation between TMB and PC3, representing Native American ancestry (P = 9 x 10-7; coef. = -.02). This finding is in line with previous studies focusing on East Asian populations. No correlation was found with SCNA burden or aneuploidy.

The incidence of EGFR somatic lung adenocarcinoma mutations are 14% in Argentina; 25% to 34% in Colombia, Brazil, and Mexico; and 51% in Peru, compared with approximately 45% in Eastern Asia.^2-4

“Despite the differences in patterns of somatic mutation between lung adenocarcinoma from patients of different ethnicity, the landscape of ancestry effects on the lung cancer genomes for the Latin American populations has not been comprehensively described; it remains unknown whether the differences are due to ancestry-specific germline variation, or rather to population-specific environmental exposures,” wrote the study authors. “This is of particular importance, as Native American ancestry—which includes components of East Asian ancestry derived through waves of migration—is present to varying degrees in modern populations in Latin America, along with European and African ancestry.”

Investigators performed a genomic analysis of 601 cases of lung cancer from Mexico and 552 from Colombia, 499 of which included self-reported non-smokers. Investigators found that 48% of patient samples (n = 552) harbored oncogenic mutations in EGFR, KRAS, BRAF, ERBB2, TP53, STK11, KEAP1, SMARCA4, SETD2, MYC, and MDM2.

In patients from Mexico, EGFR and KRAS were detected at a frequency of 30% and 10%, respectively. The mutations were also detected at a frequency of 23% and 13%, respectively, in patients from Colombia. Through the SCNA analysis, high-level MYC and MDM2 amplifications were observed in 9% and 2% of patients, respectively.

In order to better understand this relationship between ancestry and exposure-induced mutagenesis in the risk of developing lung adenocarcinoma through certain pathway activations, investigators examined ancestry associations with RTK, RAS, and RAF pathway alterations. They found that the positive correlation of Native American ancestry with EGFR mutations (odds ratio [OR], 1.23 in every 10% increase of NAT ancestry; 95% CI, 1.12-1.35), as well as the negative correlation between Native American ancestry and KRAS mutations (OR, 0.85 in every 10% increase of Native American ancestry; 95% CI, 0.77-0.95) continued to have significance.

In an analysis that was restricted to self-reported never smokers, investigators observed an association with Native American ancestry and EGFR mutations (OR, 1.46 in every 10% increase of Native American ancestry; 95% CI, 1.25-1.70). Self-reported smokers were found to have the same association (OR, 1.45 in every 10% increase of Native American ancestry; 95% CI, 1.08-1.94).

The KRAS-mutation rate was found to increase when smokers were included in the analysis in proportion to the smoking signature (OR, 1.27 in every 10% increase of smoking signature; 95% CI, 1.04-1.56). While ancestry's effect on KRAS mutations in self-reported never-smokers were noted as trending towards significance though were ultimately found to not be significant (P = .08), investigators believe that this could be due in part to the study's small sample size (n = 387).

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 Discov. 2021;11(3). doi:10.1158/2159-8290.CD-20-1165
2. Raez LE, Cardona AF, Arrieta O, et al. Lung cancer disparities in Hispanics: molecular diagnosis and use of immunotherapy. JCO Glob Oncol. 2020;6:784-788. doi:10.1200/GO.20.00004
3. Grimbrone NT, Sarcar B, Gordian ER, et al. Somatic mutations and ancestry markers in Hispanic lung cancer patients. J Thorac Oncol. 2017;12(12):1851-1856. doi:10.1016/j.jtho.2017.08.019
4. Leal LF, de Paula FE, De Marchi P, et al. Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations. Sci Rep. 2019;9:3209. doi:10.1038/s41598-019-39965-x