TY - JOUR
T1 - Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease
AU - Branford, Susan
AU - Wang, Paul
AU - Yeung, David
AU - Thomson, Daniel
AU - Purins, Adrian
AU - Wadham, Carol
AU - Shahrin, Nur Hezrin
AU - Marum, Justine E.
AU - Nataren, Nathalie
AU - Parker, Wendy T.
AU - Geoghegan, Joel
AU - Feng, Jinghua
AU - Shanmuganathan, Naranie
AU - Mueller, Martin C.
AU - Dietz, Christian
AU - Stangl, Doris
AU - Donaldson, Zoe
AU - Altamura, Haley
AU - Georgievski, Jasmina
AU - Braley, Jodi
AU - Brown, Anna
AU - Hahn, Christopher
AU - Walker, Ieuan
AU - Kim, Soo Hyun
AU - Choi, Soo Young
AU - Park, Sa Hee
AU - Kim, Dong Wook
AU - White, Deborah
AU - Yong, Agnes
AU - Ross, David M.
AU - Scott, Hamish S.
AU - Schreiber, Andreas W.
AU - Hughes, Timothy
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/8/30
Y1 - 2018/8/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052595982&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-02-832253
DO - 10.1182/blood-2018-02-832253
M3 - Article
C2 - 29967129
AN - SCOPUS:85052595982
SN - 0006-4971
VL - 132
SP - 948
EP - 961
JO - Blood
JF - Blood
IS - 9
ER -