Copy Number Amplification of the PIK3CA Gene Is Associated with Poor Prognosis in Non-lymph node metastatic Head and Neck Squamous Cell Carcinoma

Abstract

BackgroundDeregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC).MethodsWe examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients.We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis.ResultsWe examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.2%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026)ConclusionsCopy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.

Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

“…For the first time, we found that PIK3CA amplification was associated with significantly decreased PFS, whereas PIK3CA mutation was not associated with survival outcomes. Prior smaller studies were unable to identify a significant correlation between PI3K pathway activation and survival outcomes (9,15,17) and did not distinguish the relative contribution of various mechanisms of activation of the PI3K pathway (e.g., PIK3CA mutation vs. amplification vs. PTEN loss; 15). One study identified that PIK3CA amplification in 32% of 115 surgical HNSCC cases was associated with earlier relapse in a subset of patients without lymph node metastases (n ¼ 59, P ¼ 0.026; 17).…”

EGFR Inhibitors as Therapeutic Agents in Head and Neck Cancer

“…Mutational activation of KRAS only occurred in 2.6 % of 115 clinical specimens of SCCHN, although copy number amplification of KRAS was found in 10 samples (8.7 %) in the same study [229]. In another study, KRAS mutations were found in 4 out of 29 patients with SCCHN and the presence of the G12V KRAS mutation was associated with an absence of response to cetuximab and radiotherapy [230].…”

PIK3CAGene Mutations and Amplifications in Chinese Patients With Ovarian Clear Cell Carcinoma

“…PIK3CA mutations and amplification occurred independently of each other. Several reports on other carcinomas also reported that the indicated PIK3CA mutations and amplifications were mutually exclusive, suggesting that both alterations may have equivalent oncogenic potential to drive tumor carcinogenesis (24,33,34).…”

“…The PIK3CA gene copy number was calculated by dividing its value by PIK3CA Alteration in Ovarian Carcinoma  the β-actin value. Positive PIK3CA gene amplification was defined by a copy number of ≥4, as in previous studies (18,(24)(25)(26).…”