title: 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). 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 phosphoinositide 3-kinase (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 human papillomavirus-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 noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
authors.affiliation: Departments of 1Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hedberg
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Bhavana S
authors.initials: BS
authors.lastname: Vangara
authors.forename: Kelsey
authors.initials: K
authors.lastname: Pendleton
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: Breean R
authors.initials: BR
authors.lastname: Gilbert
authors.forename: Maria
authors.initials: M
authors.lastname: Freilino
authors.forename: Sam
authors.initials: S
authors.lastname: Sauerwein
authors.forename: Noah D
authors.initials: ND
authors.lastname: Peyser
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.forename: Brenda
authors.initials: B
authors.lastname: Diergaarde
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.forename: Raja
authors.initials: R
authors.lastname: Seethala
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Johnson
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Marjorie
authors.initials: M
authors.lastname: Romkes
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nukui
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwok-Shing Ng
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D011804:Quinolines / Q000008:administration & dosage; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor; D007093:Imidazoles; D011804:Quinolines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C531198:dactolisib