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

Susan Branford, Paul Wang, David T. Yeung, Daniel Thomson, Adrian Purins, Carol Wadham, Nur Hezrin Shahrin, Justine E. Marum, Nathalie Nataren, Wendy T. Parker, Joel Geoghegan, Jinghua Feng, Naranie Shanmuganathan, Martin C. Mueller, Christian Dietz, Doris Stangl, Zoe Donaldson, Haley Altamura, Jasmina Georgievski, Jodi Braley, Anna Brown, Christopher Hahn, Ieuan Walker, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Deborah L. White, Agnes S. M. Yong, David M. Ross, Hamish S. Scott, Andreas W. Schreiber and Timothy P. Hughes

Key points

  • Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes.

  • All patients at blast crisis had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in the majority.


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, IKZF1 and 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.

  • Submitted February 26, 2018.
  • Accepted June 20, 2018.