Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations

Abstract

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.

Figure 1

EGFR mutations and exon distribution. EGFR protein structure highlighting the tyrosine kinase domain (red), which is the hotspot region (red) for the EGFR mutations with predictive value. All resistance and sensitizing mutations detected in the present series of Brazilian lung adenocarcinoma are presented. *Controversial results in the literature.

Figure 2

Individual ancestry proportion of Brazilian lung adenocarcinoma series (n = 427 out of 444). The pinkish-orange, green, blue and purple colors represent the Asian, African, European and Native American ancestry proportions, respectively.

Figure 3

Kaplan-Meier curves for overall survival of lung adenocarcinoma patients (stage IV) according to EGFR mutations categorized by exon distribution (Median OS exon 19 = 19.5 months; Median OS exon 20 = 5.2 months; Median OS exon 21 = 9.3 months). Survival time is presented in months; p values are related to Log-rank test results. Exon 18 was not included in the analysis because only one patient with disease stage IV carries EGFR exon 18 mutation.