Frequent Mutation of the PI3K Pathway in Head and Neck Cancer Defines Predictive Biomarkers

Abstract

Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC)(1, 2). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the PI3K pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of HPV-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and non-canonical PIK3CA mutations were sensitive to an m-TOR/PI3K inhibitor (BEZ-235) in contrast to PIK3CA wildtype tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

“…Interestingly, the p.R88Q mutation identified in one of our HPV-positive samples (HPV?_4) was found in one tumor in the TCGA dataset, a HPVpositive sample (ID# TCGA-CR-6471) that also had a p.M1043V mutation. The p.R88Q (COSM746) and p.M1043V (COSM12591) have been reported in other cancers [27,28], but to the best of our knowledge, not as co-occurring in a HNSCC tumor. There was no evidence of the p.M1043V mutation in our HPV?_4 specimen, and therefore the p.R88Q may be recurrent in a minor population of HPV-positive tumors.…”

“…However, these technologies have had little impact on standard methods for diagnosis and treatment of HNSCC and many other types of cancer with one or more known mutational or copy number drivers. Despite extensive literature of differential gene expression profiles, mutations and copy number abnormalities in head and neck tumors that could potentially impact future clinical applications, little other than HPV status is done routinely upon diagnosis [7,10,11,13,15,24,32,[35][36][37][38][39][40][41][42][43][44][45][46][47]. A main factor contributing to this lack of progress is that no clear directives or actionable guidelines have been adopted for molecularly profiling HNSCCs.…”

“…With several highly cited genomic studies in head and neck tumors and a soon to be released TCGA study, it is clear that there is an opportunity to identify mutation, copy number and differential gene expression in these tumors to better inform treatment and prognosis than by HPV status alone [27][28][29][48][49][50][51]. The mutational spectrum shown in the HPV-negative tumors of this small study demonstrated a high mutational burden in these tumors and a source of potential difficulty in interpreting and reporting using exome or many ([100) gene diagnostic panels which could yield hundreds or thousands of variant calls.…”

“…Some of these mutations appear to be more commonly observed in HPVpositive OPSCC [53]. In addition, some of these biomarkers have been shown to be possible predictors of certain therapeutic options in SCCHN [42]. In addition to mutation data, however, we acknowledge that somatic copy number change is a crucial disease mechanism in HNSCC [28,43].…”

Resistência de células de carcinoma epidermóide bucal à terapia fotodinâmica mediada pelo ácido 5-aminolevulínico

“…Essa via é considerada a mais frequentemente mutada em carcinoma epidermóide de cabeça e pescoço (Liu et al, 2013). Mutações inativando PTEN têm sido relatadas nessa neoplasia, as quais induzem à regulação positiva de Akt (Simpson et al, 2015).…”