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Article: Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers

TitleFrequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers
Authors
Issue Date2013
Citation
Cancer Discovery, 2013, v. 3 n. 7, p. 761-769 How to Cite?
AbstractGenomic 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. Patientderived 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. SIGNIFICANCE: Treatment options for HNSCC are limited, in part, because of an incomplete understanding of the targetable mutations that "drive" tumor growth. Here, we define a subgroup of HNSCC harboring activating mutations of genes in the PI3K pathway where targeting the pathway shows antitumor efficacy. These results suggest that PI3K pathway mutation assessment may be used to guide HNSCC therapy. © 2013 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/194512
ISSN
2015 Impact Factor: 19.783
2015 SCImago Journal Rankings: 5.326
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLui, VWY-
dc.contributor.authorHedberg, ML-
dc.contributor.authorLi, H-
dc.contributor.authorVangara, BS-
dc.contributor.authorPendleton, K-
dc.contributor.authorZeng, Y-
dc.contributor.authorLu, Y-
dc.contributor.authorZhang, Q-
dc.contributor.authorDu, Y-
dc.contributor.authorGilbert, BR-
dc.contributor.authorFreilino, M-
dc.contributor.authorSauerwein, S-
dc.contributor.authorPeyser, ND-
dc.contributor.authorXiao, D-
dc.contributor.authorDiergaarde, B-
dc.contributor.authorWang, L-
dc.contributor.authorChiosea, S-
dc.contributor.authorSeethala, R-
dc.contributor.authorJohnson, JT-
dc.contributor.authorKim, S-
dc.contributor.authorDuvvuri, U-
dc.contributor.authorFerris, RL-
dc.contributor.authorRomkes, M-
dc.contributor.authorNukui, T-
dc.contributor.authorNg, PK-S-
dc.contributor.authorGarraway, LA-
dc.contributor.authorHammerman, PS-
dc.contributor.authorMills, GB-
dc.contributor.authorGrandis, JR-
dc.date.accessioned2014-01-30T03:32:40Z-
dc.date.available2014-01-30T03:32:40Z-
dc.date.issued2013-
dc.identifier.citationCancer Discovery, 2013, v. 3 n. 7, p. 761-769-
dc.identifier.issn2159-8274-
dc.identifier.urihttp://hdl.handle.net/10722/194512-
dc.description.abstractGenomic 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. Patientderived 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. SIGNIFICANCE: Treatment options for HNSCC are limited, in part, because of an incomplete understanding of the targetable mutations that "drive" tumor growth. Here, we define a subgroup of HNSCC harboring activating mutations of genes in the PI3K pathway where targeting the pathway shows antitumor efficacy. These results suggest that PI3K pathway mutation assessment may be used to guide HNSCC therapy. © 2013 American Association for Cancer Research.-
dc.languageeng-
dc.relation.ispartofCancer Discovery-
dc.titleFrequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/2159-8290.CD-13-0103-
dc.identifier.pmid23619167-
dc.identifier.scopuseid_2-s2.0-84880259398-
dc.identifier.volume3-
dc.identifier.issue7-
dc.identifier.spage761-
dc.identifier.epage769-
dc.identifier.isiWOS:000321615600024-

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