TY - JOUR
T1 - Recurrent genetic defects on chromosome 5q in myeloid neoplasms
AU - Hosono, Naoko
AU - Makishima, Hideki
AU - Mahfouz, Reda
AU - Przychodzen, Bartlomiej
AU - Yoshida, Kenichi
AU - Jerez, Andres
AU - LaFramboise, Thomas
AU - Polprasert, Chantana
AU - Clemente, Michael J.
AU - Shiraishi, Yuichi
AU - Chiba, Kenichi
AU - Tanaka, Hiroko
AU - Miyano, Satoru
AU - Sanada, Masashi
AU - Cui, Edward
AU - Verma, Amit K.
AU - McDevitt, Michael A.
AU - List, Alan F.
AU - Saunthararajah, Yogen
AU - Sekeres, Mikkael A.
AU - Boultwood, Jacqueline
AU - Ogawa, Seishi
AU - Maciejewski, Jaroslaw P.
N1 - Funding Information:
This work was supported by National Institutes of Health (R01 HL082983, U54 RR019391 and K24 HL077522 to JPM, U54 RR019391 to MAS); AA & MDS International Foundation to HM; American Cancer Society Research Scholar Grant 123436-RSG-12-159-01-DMC (to TL); and the Edward P. Evans Foundation (to MAS and JPM).
PY - 2017
Y1 - 2017
N2 - Background: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. Materials and Methods: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. Findings: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. Interpretation: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.
AB - Background: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. Materials and Methods: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. Findings: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. Interpretation: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.
KW - Del(5q)
KW - G3BP1
KW - MDS
KW - TP53
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U2 - 10.18632/oncotarget.14130
DO - 10.18632/oncotarget.14130
M3 - Article
C2 - 28031539
AN - SCOPUS:85010825665
SN - 1949-2553
VL - 8
SP - 6483
EP - 6495
JO - Oncotarget
JF - Oncotarget
IS - 4
ER -