期刊
CANCER CELL
卷 27, 期 2, 页码 298-311出版社
CELL PRESS
DOI: 10.1016/j.ccell.2015.01.002
关键词
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资金
- DFG [Ge539/12-1, Me917/20-1]
- Wilhelm-Sander-Stiftung
- BMBF Competence Network Paediatric Oncology and Haematology
- [HIPO_H025]
- Cancer Research UK [17297] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1405, W1090] Funding Source: researchfish
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX/and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.
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