Title: Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation.
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
Published In Mol Cancer Ther, (2018 07)
Abstract: 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 (NSD1), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in NSD1-mutated versus non-mutated patients, can be validated in an independent cohort. NSD1 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 NSD1 plays a causal role in these associations, we use CRISPR-Cas9 to disrupt NSD1 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 IC50 value. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function NSD1 mutations have an average 23% decrease in cisplatin IC50 value compared with cell lines with wild-type NSD1Significance: This study identifies a favorable subtype of HPV-negative HNSCC linked to NSD1 mutation, hypomethylation, and cisplatin sensitivity. Mol Cancer Ther; 17(7); 1585-94. ©2018 AACR.
PubMed ID: 29636367
MeSH Terms: CRISPR-Cas Systems/genetics; Carcinoma, Squamous Cell/drug therapy*; Carcinoma, Squamous Cell/genetics; Carcinoma, Squamous Cell/pathology; Cell Line, Tumor; Cisplatin/pharmacology; CpG Islands/drug effects; DNA Methylation/drug effects; DNA Methylation/genetics*; Drug Resistance, Neoplasm/genetics; Female; Gene Expression Regulation, Neoplastic/drug effects; Head and Neck Neoplasms/drug therapy*; Head and Neck Neoplasms/genetics; Head and Neck Neoplasms/pathology; Histone Methyltransferases; Humans; Intracellular Signaling Peptides and Proteins/genetics*; Male; Mutation/drug effects; Nuclear Proteins/genetics*; Papillomaviridae