Frequent Copy Gain of the <i>MET</i> Gene in Hypopharyngeal and Laryngeal Cancer in the Japanese Population

Abstract

Molecular targeting therapy to specific genetic alterations has not been established in head and neck squamous cell carcinoma (HNSCC) except for cetuximab treatment. To characterize alterations of actionable oncogenes in HNSCC, we examined the gain of copy and mutation of the MET gene in 54 Japanese HNSCC. Copy gain of the MET was analyzed by droplet digital PCR (ddPCR) and quantitative real time PCR (qPCR) using 2 distinct fragments of the gene, and mutation was examined in exons 14 - 19 of MET by Sanger sequencing. Both ddPCR and qPCR showed significantly correlated results in copy number at two distinct fragments of the MET gene (R = 0.96 and R = 0.78), although ddPCR gave more significant and sensitive results. Copy gain of the MET was detected in 10 of 54 (19%) HNSCCs and more frequently observed in tumors of the hypopharynx (4 of 12; 33%) or larynx (5 of 13; 38%) than those of the oral cavity (1 of 21; 4%) or oropharynx (0 of 8; 0%), suggesting the existence of site-specific features in the oncogenic mechanisms of HNSCCs. Copy gain of the MET was also observed preferentially in older patients, although no correlation in other parameters, including clinical stages and overall or recurrence-free survival, was observed. On the other hand, of the two HNSCCs in which nucleotide substitution was detected, one was R1040Q in exon 15 with unknown function, and the other was a silent mutation in exon16. These results suggest that copy gain of the MET can provide an indicator for treatment with tyrosine kinase inhibitors for MET in a subset of hypopharyngeal or laryngeal cancer.