Abstract
Objective: Molecular targeting therapy has not been generally established in head and neck squamous cell carcinoma (HNSCC) except for cetuximab treatment for targeting epidermal growth factor receptor (EGFR). We analyzed alterations of the TP53, KRAS2, and EGFR genes in Japanese HNSCC to identify subpopulations of tumors potentially susceptible or not susceptible to specific therapy based on their genetic alterations. Materials and Methods: A total of 56 Japanese subjects were included in this study. Genomic DNA of exons 5 - 9 of the TP53, exons 1 and 2 of the KRAS2, exons 19 - 22 of the EGFR, and their flanking sequences were amplified by polymerase chain reaction (PCR) followed by direct sequencing. Splicing variants of EGFR were examined by reverse transcription (RT)-PCR. Results: Mutations of the TP53 and KRAS genes were detected in 25 (45%) and 2 (4%) of 56 HNSCC cases, respectively, while neither mutation nor splicing variant of EGFR was observed. The TP53 mutation did not correlate with clinical stages or primary sites of the tumors. The patterns of nucleotide substitutions specific to HNSCC were not observed. However, the incidence of null-type mutations of the TP53, which cannot be detected as abnormal by conventional immunohistochemical (IHC) studies, was significantly higher (10/25; 40%) than that of HNSCC reported in other countries. Conclusion: Frequent TP53 mutations, especially null-type mutations, but infrequent or no alterations of the KRAS and EGFR suggest that the sequencing analysis of theTP53 mutation rather than IHC analysis of p53 provides a potentially useful marker to predict the response of HNSCC to chemotherapy or radiotherapy.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) account for 6% of all cancers worldwide, affecting more than 650,000 patients every year
None of the other 48 HNSCCs shows any KRAS mutation, suggesting that the KRAS mutation could not provide a practical marker for predicting response to cetuximab treatment in Japanese HNSCCs except for oropharyngeal squamous cell carcinomas (SCCs)
To assess the genetic markers for molecular targeting and gene-based therapy, mutations of the epidermal growth factor receptor (EGFR), KRAS, and TP53 genes were examined in 56 Japanese HNSCCs
Summary
Head and neck squamous cell carcinomas (HNSCCs) account for 6% of all cancers worldwide, affecting more than 650,000 patients every year. Most of these cases are classified as the advanced stage III/IV, which is characterized by a poor prognosis with a survival rate of only 40% and little improvement with multi-modality therapy [1] [2]. To improve the effectiveness of the molecular targeting therapies, it is important to identify biomarkers related to clinical gains. Presence of the KRAS gene mutation has been established as a useful indicator for predicting poor response to cetuximab treatment in colorectal cancer [3]. Neither screening nor extensive analyses of the KRAS gene mutation have been performed, at least not in Japanese cases of NHSCC
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