Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation

Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with worse expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nu...

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Bibliographic Details
Published in:	Molecular cancer therapeutics Vol. 17; no. 7; pp. 1585 - 1594
Main Authors:	Bui, Nam, Huang, Justin K, Bojorquez-Gomez, Ana, Licon, Katherine, Sanchez, Kyle S, Tang, Sean N, Beckett, Alex N, Wang, Tina, Zhang, Wei, Shen, John Paul, Kreisberg, Jason F, Ideker, Trey
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research Inc 01-07-2018
Subjects:	Biotechnology Cancer Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Cell Line, Tumor Chemotherapy Cisplatin Cisplatin - pharmacology CpG islands CpG Islands - drug effects CRISPR CRISPR-Cas Systems - genetics DNA Methylation - drug effects DNA Methylation - genetics Drug Resistance, Neoplasm - genetics Female Gene Expression Regulation, Neoplastic - drug effects Genomes Head Head & neck cancer Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - genetics Head and Neck Neoplasms - pathology Histone methyltransferase Human papillomavirus Humans Intracellular Signaling Peptides and Proteins - genetics Male Mutation Mutation - drug effects Nuclear Proteins - genetics Papillomaviridae Patients Proteins Sensitivity Squamous cell carcinoma Tumor cell lines Tumors
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Summary:	Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with worse expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nuclear Set Domain Containing Protein 1 ( ), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in -mutated versus non-mutated patients, can be validated in an independent cohort. alterations are strongly associated with widespread genome hypomethylation in the same tumors, to a degree not observed for any other mutated gene. To address whether plays a causal role in these associations, we use CRISPR-Cas9 to disrupt in HNSCC cell lines and find that this leads to substantial CpG hypomethylation and sensitivity to cisplatin, a standard chemotherapy in head and neck cancer, with a 40% to 50% decrease in the IC value. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function mutations have an average 23% decrease in cisplatin IC value compared with cell lines with wild-type This study identifies a favorable subtype of HPV-negative HNSCC linked to mutation, hypomethylation, and cisplatin sensitivity. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 John Paul Shen, M.D., UC San Diego, Department of Medicine, 9500 Gilman Drive MC-0688, La Jolla, CA 92093-0688, (858) 822-4704 Trey Ideker, Ph.D., UC San Diego, Department of Medicine, 9500 Gilman Drive MC-0688, La Jolla, CA 92093-0688, (858) 822-4558 Jason F. Kreisberg, Ph.D., UC San Diego, Department of Medicine, 9500 Gilman Drive MC-0688, La Jolla, CA 92093-0688, (858) 534-3578 Equal contributions Contact Information
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.MCT-17-0937