domingo, 15 de julio de 2018

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease. - PubMed - NCBI

2018 Jul 2. pii: blood-2018-02-832253. doi: 10.1182/blood-2018-02-832253. [Epub ahead of print]

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease.

Branford S1, Wang P2, Yeung DT3, Thomson D2, Purins A2, Wadham C2, Shahrin NH2, Marum JE2, Nataren N2, Parker WT4, Geoghegan J5, Feng J5, Shanmuganathan N2, Mueller MC6, Dietz C6, Stangl D2, Donaldson Z2, Altamura H2, Georgievski J2, Braley J2, Brown A2, Hahn C2, Walker I7, Kim SH8, Choi SY9, Park SH9, Kim DW10, White DL11, Yong ASM12, Ross DM13, Scott HS2, Schreiber AW14, Hughes TP15.

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Abstract

Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1, IKZF1and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia translocation was detected at diagnosis in 11/46 patients (24%) comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9/27 (33%) versus 2/19 optimal responders (11%), P=.07. Thirty-nine patients were tested at BC and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations co-occurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Philadelphia translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.