Disruption of 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 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. .