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Mol Cancer Ther. 2018 Jul;17(7):1585-1594. doi: 10.1158/1535-7163.MCT-17-0937. Epub 2018 Apr 10.

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

Author information

1
Department of Medicine, UC San Diego, La Jolla, California.
2
Bioinformatics and Systems Biology Program, UC San Diego, La Jolla, California.
3
Department of Medicine, UC San Diego, La Jolla, California. tideker@ucsd.edu jpshen@ucsd.edu jkreisberg@ucsd.edu.
4
Department of Bioengineering, UC San Diego, La Jolla, California.
#
Contributed equally

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.

PMID:
29636367
PMCID:
PMC6030464
[Available on 2019-07-01]
DOI:
10.1158/1535-7163.MCT-17-0937

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