Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Adam J
AJ
de Smith
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Juhi
J
Ojha
Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Stephen S
SS
Francis
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Erica
E
Sanders
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Alyson A
AA
Endicott
Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Helen M
HM
Hansen
Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Ivan
I
Smirnov
Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Amanda M
AM
Termuhlen
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.|Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Kyle M
KM
Walsh
School of Public Health, University of California Berkeley, Berkeley, California, United States of America.
Catherine
C
Metayer
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.|Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Joseph L
JL
Wiemels
D060965:Clonal Evolution / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D009857:Oncogenes; D011123:Polyploidy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D018631:ras Proteins
DOT1L; high hyperdiploid acute lymphoblastic leukemia; microclonal mutations; targeted deep-sequencing; tumor heterogeneity
Cancer Res. 2006 Aug 1;66(15):7473-81
16885344
N Engl J Med. 2010 Dec 16;363(25):2424-33
21067377
Blood. 2005 Jan 1;105(1):335-40
15345593
Nucleic Acids Res. 2015 Jan;43(Database issue):D805-11
25355519
J Clin Invest. 2013 Jul;123(7):3099-111
23921123
JAMA. 2003 Sep 24;290(12):1583-92
14506117
Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):578-81
16537719
Cell. 2007 Dec 14;131(6):1190-203
18083107
Blood. 2013 Nov 7;122(19):3298-307
23996088
Cancer Cell. 2015 Apr 13;27(4):502-15
25873173
Clin Cancer Res. 2013 Aug 1;19(15):4040-5
23719267
Blood. 2004 Jul 15;104(2):307-13
14982869
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19069-74
16354839
Hum Mol Genet. 2009 Nov 1;18(21):4054-65
19679565
PLoS Genet. 2013 Jun;9(6):e1003542
23754963
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):916-21
12538861
Leukemia. 2012 Aug;26(8):1797-803
22388726
Clin Cancer Res. 2015 May 15;21(10):2348-58
25688158
Blood. 2003 Oct 15;102(8):3010-5
12829594
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21719-24
21098271
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
27100738
Cell Cycle. 2014;13(5):726-38
24526115
Nat Genet. 2015 Jun;47(6):672-6
25961940
Nature. 2011 Mar 10;471(7337):235-9
21390130
Cancer Cell. 2016 Aug 8;30(2):363-365
27505680
Genes Chromosomes Cancer. 2008 Jan;47(1):26-33
17910045
Leukemia. 2016 May;30(5):1194-7
26437776
J Biol Chem. 2012 Feb 17;287(8):5588-99
22190683
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19519-24
24218589
Nat Genet. 2001 Dec;29(4):465-8
11704759
Cell Rep. 2014 Jan 16;6(1):130-40
24388756
Nat Commun. 2015 Mar 19;6:6604
25790293
Nature. 2012 Jan 11;481(7380):157-63
22237106
Blood. 1992 Jul 1;80(1):203-8
1351763
BMC Cancer. 2015 Sep 07;15:621
26345285
Blood. 2008 Jun 15;111(12):5515-23
18334672
Clin Cancer Res. 2015 Mar 1;21(5):1087-97
25248381
Blood. 2002 Jul 1;100(1):347-9
12070048
Nat Genet. 2009 Sep;41(9):1001-5
19684603
Nat Genet. 2007 Mar;39(3):347-51
17293865
Stem Cells. 2009 Jul;27(7):1538-47
19544450
BMC Cancer. 2010 Sep 27;10:513
20875128
Blood. 2013 Jun 6;121(23 ):4808-9
23744494
Nat Genet. 2014 Mar;46(3):310-5
24487276
N Engl J Med. 2012 Mar 22;366(12):1079-89
22417203
Leukemia. 2016 May;30(5):1025-32
26686245
Leukemia. 2015 Aug;29(8):1656-67
25917266
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18250-5
24145436
Leukemia. 2008 Sep;22(9):1692-7
18548099
Genes Chromosomes Cancer. 2009 Aug;48(8):637-60
19415723
Int J Epidemiol. 2010 Dec;39(6):1628-37
20889538
Blood. 2010 Nov 25;116(22):4483-91
20798234
Nat Commun. 2014 Apr 08;5:3630
24710217
Blood Cancer J. 2015 Oct 16;5:e361
26473533
Cancer Cell. 2011 Jul 12;20(1):66-78
21741597
Leukemia. 2005 Mar;19(3):415-9
15674422
N Engl J Med. 2015 Dec 10;373(24):2336-46
26580448
Nucleic Acids Res. 2015 Mar 11;43(5):2590-602
25690899
PLoS One. 2011;6(5):e19541
21602921
Blood. 2014 Nov 27;124(23):3420-30
25253770