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Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus–positive oropharyngeal squamous cell carcinoma
Author(s) -
Haft Sunny,
Ren Shuling,
Xu Guorong,
Mark Adam,
Fisch Kathleen,
Guo Theresa W.,
Khan Zubair,
Pang John,
Ando Mizuo,
Liu Chao,
Sakai Akihiro,
Fukusumi Takahito,
Califano Joseph A.
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32068
Subject(s) - medicine , human papillomavirus , chromatin , basal cell , cancer research , pathology , oncology , biology , genetics , gene
Background Human papillomavirus (HPV)–associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking‐related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied. Methods This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort. Results There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C ( KMT2C ), lysine methyltransferase 2D ( KMT2D ), nuclear receptor binding SET domain protein 1 ( NSD1 ), CREB binding protein ( CREBBP ), E1A‐associated protein p300 ( EP300 ), and CCCTC‐binding factor ( CTCF ). In addition, the commonly altered genes phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit α ( PIK3CA ) and fibroblast growth factor receptor 3 ( FGFR3 ) showed distinct domain‐specific hotspot mutations in comparison with their HPV– counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV– HNSCC. Conclusions This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone‐ and chromatin‐modifying genes, which may offer novel therapeutic targets.

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