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Relapsed Neuroblastomas Show Frequent RAS-MAPK Pathway Mutations
Oleh:
Eleveld, Thomas F.
;
Oldridge, Derek A.
;
Bernard, Virginie
;
Koster, Jan
;
Daage, Leo Colmet
Jenis:
Article from Journal - ilmiah internasional
Dalam koleksi:
Nature Genetics vol. 47 no. 08 (Aug. 2015)
,
page 864–871.
Topik:
Targeted Therapies
Ketersediaan
Perpustakaan FK
Nomor Panggil:
N12.K
Non-tandon:
1 (dapat dipinjam: 0)
Tandon:
tidak ada
Lihat Detail Induk
Isi artikel
The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
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