Τρίτη 10 Απριλίου 2018

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 poor 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 - 50% decrease in IC50. 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 compared to cell lines with wild type NSD1. This study identifies a favorable subtype of head and neck cancer linked to NSD1 mutation, hypomethylation and cisplatin sensitivity.



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