Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease
| Autor: | Martin C. Mueller, David M. Ross, David T Yeung, Andreas W. Schreiber, Timothy P. Hughes, Daniel Thomson, Jodi Braley, Nur Hezrin Shahrin, Wendy T Parker, Agnes S. M. Yong, Deborah L. White, Christian Dietz, Naranie Shanmuganathan, Jasmina Georgievski, Soo-Hyun Kim, Carol Wadham, Susan Branford, Dong-Wook Kim, Anna L. Brown, Joel Geoghegan, Adrian Purins, Justine E Marum, Jinghua Feng, Soo Young Choi, Christopher N. Hahn, Nathalie Nataren, Doris Stangl, Paul Wang, Hamish S. Scott, Haley Altamura, Sa-Hee Park, Ieuan Walker, Zoe R. Donaldson |
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| Přispěvatelé: | Branford, Susan, Wang, Paul, Yeung, David T, Thomson, Daniel, Wadham, Carol, Shahrin, Nur Hezrin, Marum, Justine E, Nataren, Nathalie, Parker, Wendy T, Shanmuganathan, Naranie, Donaldson, Zoe, Altamura, Haley, Georgievski, Jasmina, Brown, Anna, Hahn, Christopher, White, Deborah L, Scott, Hamish S, Schreiber, Andreas W, Hughes, Timothy P |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology Adult Male medicine.medical_specialty genomic events Adolescent Immunology Chromosomal translocation Philadelphia chromosome Biochemistry Disease-Free Survival Translocation Genetic 03 medical and health sciences 0302 clinical medicine Risk Factors Internal medicine Leukemia Myelogenous Chronic BCR-ABL Positive Biomarkers Tumor Medicine Humans Philadelphia Chromosome chronic myeloid leukemia (CML) Gene Exome sequencing Aged Aged 80 and over ABL business.industry Cancer Cell Biology Hematology Genomics therapeutic approach Middle Aged medicine.disease Neoplasm Proteins Survival Rate Leukemia 030104 developmental biology 030220 oncology & carcinogenesis Biomarker (medicine) Female business Follow-Up Studies |
| Zdroj: | Blood. 132(9) |
| ISSN: | 1528-0020 |
| Popis: | 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 sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders (P 5 .007). Frequently mutated genes at diagnosis were ASXL1, IKZF1, and RUNX1. The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients 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 (33%) of 27 vs 2 (11%) of 19 optimal responders (P 5 .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations cooccurred 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 Ph 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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