Copy number gain of PIK3CA and MET is associated with poor prognosis in head and neck squamous cell carcinoma

Abstract

The incidence of head and neck squamous cell carcinomas is still growing, and the long-term prognosis of advanced disease remains poor. Only a fraction of head and neck cancers are sensitive to the EGFR-inhibitor cetuximab, which is the only registered targeted therapy available today. In several cancers, gene copy number alterations of MET and PIK3CA have been found to be prognostic and predictive for therapy response. The aim of this study was to systematically analyze in head and neck cancers the pathological characteristics and prognostic significance of copy number changes of MET and PIK3CA genes. MET and PIK3CA copy numbers were analyzed by fluorescence in situ hybridization in tumor samples of 152 patients. Expression of EGFR, p16, and Ki67 was studied by immunohistochemistry. High polysomy of PIK3CA (chromosome 3) was found in 20 % of cases and amplification in 4.5 %. Regarding MET, 35 % of cases showed low or high polysomy of the gene (chromosome 7), while no intra-chromosomal amplification of MET was detected. PIK3CA copy number gain (high polysomy or amplification) was significantly associated with shorter disease-specific survival, larger tumor volume, and lower p16 expression. MET copy number gain (low or high polysomy) in tumors was significantly associated with shorter disease-specific survival and lower level of EGFR. PIK3CA and MET may play an important role in oncogenesis of certain specific subtypes of head and neck cancer. There is an urgent need for the development of novel targeted therapies against these tumors associated with poor prognosis.

p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC

“…In support of our findings, downregulation of P120CTN has been correlated with increased stage and a higher rate of lymph node metastasis in HNSCC (30)(31)(32)(33). In addition, overexpression of PIK3CA has been linked to decreased patient survival; however, there is little known about the role of mutated PIK3CA in HNSCC disease progression (34). Aside from HNSCC, P120CTN loss or PIK3CA mutations correlate with decreased patient survival in many types of cancers (14,(35)(36)(37)(38)(39).…”

Genomic Alteration in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Inferred from Karyotyping, Molecular Cytogenetics, and Array Comparative Genomic Hybridization

“…However, most of the cell lines shared numerical aberrations with gain of chromosome 1, 7, and 11. Basically, both chromosome 7 and 11 contain genes that are involved in the tumor progression such as EGFR , HGF , HOX , BRAF , PAFAH1B2 , FLI1 , and ETS1 [ 30 – 35 ], in particular LAMB1 , MET , MMP1 , CCND1 , ORAOV1 , FADD , PPFIA1 , and CTTN genes which related to HNSCC [ 36 – 38 ]. In addition, the gain of chromosome 7 was predominantly found in colorectal cancer, glioblastoma, and renal cell carcinoma [ 32 , 39 , 40 ], and the gain of chromosome 11 was reported in ovarian cancer and myeloid leukemia [ 41 , 42 ].…”

<p>Novel genetic alterations and their impact on target therapy response in head and neck squamous cell carcinoma</p>

“…Head and neck squamous cell carcinoma (HNSCC) causes more than 300,000 deaths worldwide each year and its incidence is still growing 1. HNSCC is a fatal heterogeneous disease, with highly variable tumor sites and biologic behaviors 2.…”

“…Recent developments included US Food and Drug Administration approval of pembrolizumab and cetuximab. Cetuximab has conferred a survival advantage when combined with platinum-based combination chemotherapy in the first-line R/M setting 98. However, only a fraction of HNSCC are sensitive to the cetuximab, 5-year survival of HNSCC is not improved by the cetuximab, which is currently <40% 82,99…”