Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

Abstract

Background: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study.

Methods: Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis.

Results: EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments.

Conclusions: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and 'second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.

Figure 1

Combinations of multiple mutations. (A) Double mutation sites and case number in 153 patients. Double mutations L858R+T790M showed the highest incidence rate (9.8%, 15 out of 153) followed by L858R+E545K (8.5%, 13 out of 153). (B) Four set venn-diagram of single and multiple mutation panoramagram for the whole study.

Figure 2

Somatic mutation frequencies of EGFR, KRAS, BRAF and PIK3CA. (A) The mutation sites (abscissas) and frequency (ordinates) of EGFR, KRAS, BRAF and PIK3CA in 5125 patients with NSCLC. (B) Distributions tree-map of EGFR, KRAS, BRAF and PIK3CA mutations in 2368 patients carrying mutations.

Figure 3

(A) The bars on two sides of the horizontal axis represent the percentage difference of male and female genotypes. The bars above represent male genotypes, and the bars below represent female genotypes. The bars with a rectangle box show the statistical difference of genotypes between male and female by the binomial test (P<0.001). (B) The bars on two sides of horizontal axis represent the percentage difference of smoker and non-smoker genotypes. The above are smokers', and the below, non-smokers'. The bars with a rectangle box show the statistical difference of genotypes in percentage between smokers and non-smokers by the binomial test (P<0.001). Chart (A) and (B) share the same horizontal axis that represents genotypes.