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

Vivian W.Y. Lui, Matthew L. Hedberg, Hua Li, Bhavana S. Vangara, Kelsey Pendleton, Yan Zeng, Yiling Lu, Qiuhong Zhang, Yu Du, Breean R. Gilbert, Maria Freilino, Sam Sauerwein, Noah D. Peyser, Dong Xiao, Brenda Diergaarde, Lin Wang, Simion Chiosea, Raja Seethala, Jonas T. Johnson, Seungwon KimUmamaheswar Duvvuri, Robert L. Ferris, Marjorie Romkes, Tomoko Nukui, Patrick Kwok Shing Ng, Levi A. Garraway, Peter S. Hammerman, Gordon Mills, Jennifer R. Grandis

Research output: Contribution to journalArticle

290 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)761-769
Number of pages9
JournalCancer Discovery
Volume3
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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1-Phosphatidylinositol 4-Kinase
Head and Neck Neoplasms
Biomarkers
Mutation
Neoplasm Genes
Neoplasms
Exome
Mutation Rate
Cell- and Tissue-Based Therapy
Carcinoma, squamous cell of head and neck
Genes
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology

Cite this

Lui, V. W. Y., Hedberg, M. L., Li, H., Vangara, B. S., Pendleton, K., Zeng, Y., ... Grandis, J. R. (2013). Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discovery, 3(7), 761-769. https://doi.org/10.1158/2159-8290.CD-13-0103

Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. / Lui, Vivian W.Y.; Hedberg, Matthew L.; Li, Hua; Vangara, Bhavana S.; Pendleton, Kelsey; Zeng, Yan; Lu, Yiling; Zhang, Qiuhong; Du, Yu; Gilbert, Breean R.; Freilino, Maria; Sauerwein, Sam; Peyser, Noah D.; Xiao, Dong; Diergaarde, Brenda; Wang, Lin; Chiosea, Simion; Seethala, Raja; Johnson, Jonas T.; Kim, Seungwon; Duvvuri, Umamaheswar; Ferris, Robert L.; Romkes, Marjorie; Nukui, Tomoko; Ng, Patrick Kwok Shing; Garraway, Levi A.; Hammerman, Peter S.; Mills, Gordon; Grandis, Jennifer R.

In: Cancer Discovery, Vol. 3, No. 7, 01.07.2013, p. 761-769.

Research output: Contribution to journalArticle

Lui, VWY, Hedberg, ML, Li, H, Vangara, BS, Pendleton, K, Zeng, Y, Lu, Y, Zhang, Q, Du, Y, Gilbert, BR, Freilino, M, Sauerwein, S, Peyser, ND, Xiao, D, Diergaarde, B, Wang, L, Chiosea, S, Seethala, R, Johnson, JT, Kim, S, Duvvuri, U, Ferris, RL, Romkes, M, Nukui, T, Ng, PKS, Garraway, LA, Hammerman, PS, Mills, G & Grandis, JR 2013, 'Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers', Cancer Discovery, vol. 3, no. 7, pp. 761-769. https://doi.org/10.1158/2159-8290.CD-13-0103
Lui, Vivian W.Y. ; Hedberg, Matthew L. ; Li, Hua ; Vangara, Bhavana S. ; Pendleton, Kelsey ; Zeng, Yan ; Lu, Yiling ; Zhang, Qiuhong ; Du, Yu ; Gilbert, Breean R. ; Freilino, Maria ; Sauerwein, Sam ; Peyser, Noah D. ; Xiao, Dong ; Diergaarde, Brenda ; Wang, Lin ; Chiosea, Simion ; Seethala, Raja ; Johnson, Jonas T. ; Kim, Seungwon ; Duvvuri, Umamaheswar ; Ferris, Robert L. ; Romkes, Marjorie ; Nukui, Tomoko ; Ng, Patrick Kwok Shing ; Garraway, Levi A. ; Hammerman, Peter S. ; Mills, Gordon ; Grandis, Jennifer R. / Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. In: Cancer Discovery. 2013 ; Vol. 3, No. 7. pp. 761-769.
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AU - Lui, Vivian W.Y.

AU - Hedberg, Matthew L.

AU - Li, Hua

AU - Vangara, Bhavana S.

AU - Pendleton, Kelsey

AU - Zeng, Yan

AU - Lu, Yiling

AU - Zhang, Qiuhong

AU - Du, Yu

AU - Gilbert, Breean R.

AU - Freilino, Maria

AU - Sauerwein, Sam

AU - Peyser, Noah D.

AU - Xiao, Dong

AU - Diergaarde, Brenda

AU - Wang, Lin

AU - Chiosea, Simion

AU - Seethala, Raja

AU - Johnson, Jonas T.

AU - Kim, Seungwon

AU - Duvvuri, Umamaheswar

AU - Ferris, Robert L.

AU - Romkes, Marjorie

AU - Nukui, Tomoko

AU - Ng, Patrick Kwok Shing

AU - Garraway, Levi A.

AU - Hammerman, Peter S.

AU - Mills, Gordon

AU - Grandis, Jennifer R.

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