Mutation analysis of the EGFR pathway genes, EGFR, RAS, PIK3CA, BRAF, and AKT1, in salivary gland adenoid cystic carcinoma.

Kosuke Saida,Yoshiyuki Iida,Yasushi Yatabe,Daisuke Kawakita,Kazuo Shimozato,Takayuki Murase,Mayuko Ito,Hisashi Takino,Ken-Ichi Nibu,Nobuhiro Hanai,Kei Ijichi,Tetsuro Onitsuka,Hiroshi Inagaki,Kimihide Kusafuka,Yuichiro Tada,Yasuhisa Hasegawa,Hitomi Shinomiya,Ayako Masaki,Kana Fujii

doi:10.18632/oncotarget.24818

Abstract

Adenoid cystic carcinoma (AdCC), one of the most common salivary gland carcinomas, usually has a fatal outcome. Epidermal growth factor receptor (EGFR) pathway gene mutations are important in predicting a patient's prognosis and estimating the efficacy of molecular therapy targeting the EGFR pathway. In this study of salivary gland AdCC (SAdCC), we looked for gene mutations in EGFR, RAS family (KRAS, HRAS, and NRAS), PIK3CA, BRAF, and AKT1, using a highly sensitive single-base extension multiplex assay, SNaPshot. Out of 70 cases, EGFR pathway missense mutations were found in 13 (18.6%): RAS mutations in 10 (14.3%), EGFR in one (1.4%), and PIK3CA in 5 (7.1%). None of the cases showed an EGFR deletion by direct sequencing. Concurrent gene mutations were found in three cases (4.3%). EGFR pathway mutations were significantly associated with a shorter disease-free (p = 0.011) and overall survival (p = 0.049) and RAS mutations were as well; (p = 0.010) and (p = 0.024), respectively. The gene fusion status as determined by a FISH assay had no significant association with mutations of the genes involved in the EGFR pathway. In conclusion, EGFR pathway mutations, especially RAS mutations, may be frequent in SAdCC, and associated with a poor prognosis for the patient.

Highlights

Adenoid cystic carcinoma (AdCC), rare accounting for less than 1% of all head and neck cancers, is one of the most common carcinomas of the salivary gland [1]
We looked for gene mutations in Epidermal growth factor receptor (EGFR), RAS family (KRAS, HRAS, and NRAS), PIK3CA, BRAF, and AKT1, by SNaPshot assay, a highly sensitive single-base extension multiplex assay [31,32,33,34] and EGFR deletion was detected by direct sequencing
In examining our 70 salivary gland AdCC (SAdCC) cases, we searched for mutations in genes involved in the EGFR pathway [EGFR, RAS family (KRAS, HRAS, and NRAS), PIK3CA, BRAF, and AKT1]

Summary

Introduction

Adenoid cystic carcinoma (AdCC), rare accounting for less than 1% of all head and neck cancers, is one of the most common carcinomas of the salivary gland [1]. Factors that often influence survival include tumor stage, node status, patient age, tumor site, large nerve perineural invasion, and surgical margins. Standard treatment for this carcinoma is surgical resection followed by post-operative radiotherapy and/ or chemotherapy. Previous studies have revealed that MYBNFIB and MYBL1-NFIB fusions are major alterations in this carcinoma, accounting for approximately 50% and 10% of AdCC cases, respectively [3,4,5,6,7]. Gene alterations involving MYB, MYBL1, or NFIB genes have been considered to be among the primary events in AdCC development. Oncogenetic events associated with AdCC progression have not been well recognized

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Results

Conclusion