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

Susan Branford, Paul Wang, David 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 & 13 others Anna Brown, Christopher Hahn, Ieuan Walker, Soo Hyun Kim, Soo Young Choi, Sa Hee Park, Dong Wook Kim, Deborah White, Agnes Yong, David M. Ross, Hamish S. Scott, Andreas W. Schreiber, Timothy Hughes

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 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.

LanguageEnglish
Pages948-961
Number of pages14
JournalBlood
Volume132
Issue number9
DOIs
Publication statusPublished - 30 Aug 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Branford, Susan ; Wang, Paul ; Yeung, David ; Thomson, Daniel ; Purins, Adrian ; Wadham, Carol ; Shahrin, Nur Hezrin ; Marum, Justine E. ; Nataren, Nathalie ; Parker, Wendy T. ; Geoghegan, Joel ; Feng, Jinghua ; Shanmuganathan, Naranie ; Mueller, Martin C. ; Dietz, Christian ; Stangl, Doris ; Donaldson, Zoe ; Altamura, Haley ; Georgievski, Jasmina ; Braley, Jodi ; Brown, Anna ; Hahn, Christopher ; Walker, Ieuan ; Kim, Soo Hyun ; Choi, Soo Young ; Park, Sa Hee ; Kim, Dong Wook ; White, Deborah ; Yong, Agnes ; Ross, David M. ; Scott, Hamish S. ; Schreiber, Andreas W. ; Hughes, Timothy. / Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. In: Blood. 2018 ; Vol. 132, No. 9. pp. 948-961.
@article{7a993894f1c445fd8c36f9e553701b3c,
title = "Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease",
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 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.",
author = "Susan Branford and Paul Wang and David Yeung and Daniel Thomson and Adrian Purins and Carol Wadham and Shahrin, {Nur Hezrin} and Marum, {Justine E.} and Nathalie Nataren and Parker, {Wendy T.} and Joel Geoghegan and Jinghua Feng and Naranie Shanmuganathan and Mueller, {Martin C.} and Christian Dietz and Doris Stangl and Zoe Donaldson and Haley Altamura and Jasmina Georgievski and Jodi Braley and Anna Brown and Christopher Hahn and Ieuan Walker and Kim, {Soo Hyun} and Choi, {Soo Young} and Park, {Sa Hee} and Kim, {Dong Wook} and Deborah White and Agnes Yong and Ross, {David M.} and Scott, {Hamish S.} and Schreiber, {Andreas W.} and Timothy Hughes",
year = "2018",
month = "8",
day = "30",
doi = "10.1182/blood-2018-02-832253",
language = "English",
volume = "132",
pages = "948--961",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "9",

}

Branford, S, Wang, P, Yeung, D, Thomson, D, Purins, A, Wadham, C, Shahrin, NH, Marum, JE, Nataren, N, Parker, WT, Geoghegan, J, Feng, J, Shanmuganathan, N, Mueller, MC, Dietz, C, Stangl, D, Donaldson, Z, Altamura, H, Georgievski, J, Braley, J, Brown, A, Hahn, C, Walker, I, Kim, SH, Choi, SY, Park, SH, Kim, DW, White, D, Yong, A, Ross, DM, Scott, HS, Schreiber, AW & Hughes, T 2018, 'Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease', Blood, vol. 132, no. 9, pp. 948-961. https://doi.org/10.1182/blood-2018-02-832253

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. / Branford, Susan; Wang, Paul; Yeung, David; Thomson, Daniel; Purins, Adrian; Wadham, Carol; Shahrin, Nur Hezrin; Marum, Justine E.; Nataren, Nathalie; Parker, Wendy T.; Geoghegan, Joel; Feng, Jinghua; Shanmuganathan, Naranie; Mueller, Martin C.; Dietz, Christian; Stangl, Doris; Donaldson, Zoe; Altamura, Haley; Georgievski, Jasmina; Braley, Jodi; Brown, Anna; Hahn, Christopher; Walker, Ieuan; Kim, Soo Hyun; Choi, Soo Young; Park, Sa Hee; Kim, Dong Wook; White, Deborah; Yong, Agnes; Ross, David M.; Scott, Hamish S.; Schreiber, Andreas W.; Hughes, Timothy.

In: Blood, Vol. 132, No. 9, 30.08.2018, p. 948-961.

Research output: Contribution to journalArticle

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

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

VL - 132

SP - 948

EP - 961

JO - Blood

T2 - Blood

JF - Blood

SN - 0006-4971

IS - 9

ER -