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Disruption of NSD1 in head and neck cancer promotes favorable chemotherapeutic responses linked to hypomethylation
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-04-10 , DOI: 10.1158/1535-7163.mct-17-0937
Nam Bui 1 , Justin K. Huang 2 , Ana Bojorquez-Gomez 1 , Katherine Licon 1 , Kyle S. Sanchez 1 , Sean N. Tang 1 , Alex N. Beckett 1 , Tina Wang 1 , Wei Zhang 1 , John Paul Shen 1 , Jason F. Kreisberg 1 , Trey Ideker 1, 2, 3
Affiliation  

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 NSD1. Significance: 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.

中文翻译:

NSD1在头颈癌中的破坏促进了与低甲基化相关的有利化学治疗反应

人乳头瘤病毒 (HPV) 阴性的头颈部鳞状细胞癌 (HNSCC) 代表了一种具有更差预期结果的独特癌症分类。在 HNSCC 中反复突变的 11 个基因中,我们发现编码核集域含蛋白 1 (NSD1) 的基因突变具有单一且实质性的生存优势,NSD1 是一种在大约 10% 的患者中发生改变的组蛋白甲基转移酶。这种效果,即 NSD1 突变患者与非突变患者的死亡风险降低 55%,可以在独立队列中得到验证。NSD1 改变与相同肿瘤中广泛的基因组低甲基化密切相关,在任何其他突变基因中都没有观察到这种程度。为了解决 NSD1 是否在这些关联中起因果作用,我们使用 CRISPR-Cas9 破坏 HNSCC 细胞系中的 NSD1,发现这会导致显着的 CpG 低甲基化和对顺铂(头颈癌的标准化疗)的敏感性,IC50 值降低 40% 至 50%。对 1,001 个癌细胞系的调查证实了这样的结果,其中与具有野生型 NSD1 的细胞系相比,功能丧失 NSD1 突变的顺铂 IC50 值平均降低了 23%。意义:本研究确定了与 NSD1 突变、低甲基化和顺铂敏感性相关的 HPV 阴性 HNSCC 的有利亚型。摩尔癌症治疗; 17(7); 1585-94。©2018 AACR。其中与具有野生型 NSD1 的细胞系相比,功能丧失 NSD1 突变的顺铂 IC50 值平均降低 23%。意义:本研究确定了与 NSD1 突变、低甲基化和顺铂敏感性相关的 HPV 阴性 HNSCC 的有利亚型。摩尔癌症治疗; 17(7); 1585-94。©2018 AACR。其中与具有野生型 NSD1 的细胞系相比,功能丧失 NSD1 突变的顺铂 IC50 值平均降低 23%。意义:本研究确定了与 NSD1 突变、低甲基化和顺铂敏感性相关的 HPV 阴性 HNSCC 的有利亚型。摩尔癌症治疗; 17(7); 1585-94。©2018 AACR。
更新日期:2018-04-10
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