Braf and erbB2 mutations correlate with smoking status in lung cancer patients

Abstract

The erbB pathway involves a family of tyrosine kinases and contributes to resistance or sensitivity to chemotherapy in many tumor types. Somatic mutations of the epidermal growth factor receptor (EGFR) gene at the kinase domain have been found in lung cancer patients. These mutations are correlated with clinical response to targeted molecular therapy. Although Caucasian lung cancer patients have been shown to harbor Braf and erbB2 mutations, only a few reports exist concerning Braf and erbB2 mutations in Japanese lung cancer patients. We investigated the Braf and erbB2 mutation status in non-small cell lung cancer (NSCLC) patients by reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing. The study included 305 surgically removed lung cancer samples from the Nagoya City University Hospital, which were EGFR and Kras wild-type centric. Six Braf mutations were found in the adenocarcinoma cases. Among the adenocarcinoma cases, Braf mutations were more frequently noted in heavy smokers (Brinkman index >400, p=0.0476). We also detected five erbB2 mutations all in the non-smokers. All of these mutations existed exclusively. The erbB2 gene mutations were predominantly found in non-smokers with adenocarcinomas. However, the completely exclusive mutation status could help us design individually tailored targeted molecular therapy for lung cancer.

Figure 1.

Braf mutations in lung cancer patients. One mutation consisted of N581I (1742 adenine to thymine; asparagine to isoleucine) (upper) and five were V600E (1799 thymine to adenine; valine to glutamic acid) (lower). Reverse sequence reading was also confirmed (right).

Figure 2.

erbB2 mutations in lung cancer patients. Four cases consisted of 12 amino acid insertion mutation (2324–2325 ins ATACGTGATGGC), located in exon 20 at the kinase domain (775–776 ins YVMA) (upper). Reverse sequence for the erbB2 gene was also confirmed (right) One had an amino acid insertion mutation (2326 G to TTGT), located in exon 20 at the kinase domain (776 glycine to leucine plus cysteine) (lower). Reverse sequence reading was also confirmed (right).