Recurrent genetic defects on chromosome 5q in myeloid neoplasms

Naoko Hosono, Hideki Makishima, Reda Mahfouz, Bartlomiej Przychodzen, Kenichi Yoshida, Andres Jerez, Thomas LaFramboise, Chantana Polprasert, Michael J. Clemente, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Masashi Sanada, Edward Cui, Amit K. Verma, Michael A. McDevitt, Alan F. List, Yogen Saunthararajah, Mikkael A. SekeresJacqueline Boultwood, Seishi Ogawa, Jaroslaw P. Maciejewski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6483-6495
Number of pages13
JournalOncotarget
Volume8
Issue number4
DOIs
StatePublished - 2017

Fingerprint

Chromosome Deletion
Chromosomes
Mutation
Neoplasms
Allelic Imbalance
Clonal Deletion
Genes
Exome
Haploinsufficiency
Diploidy
Karyotype
Single Nucleotide Polymorphism
Survival

Keywords

  • Del(5q)
  • G3BP1
  • MDS
  • TP53

ASJC Scopus subject areas

  • Oncology

Cite this

Hosono, N., Makishima, H., Mahfouz, R., Przychodzen, B., Yoshida, K., Jerez, A., ... Maciejewski, J. P. (2017). Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget, 8(4), 6483-6495. https://doi.org/10.18632/oncotarget.14130

Recurrent genetic defects on chromosome 5q in myeloid neoplasms. / Hosono, Naoko; Makishima, Hideki; Mahfouz, Reda; Przychodzen, Bartlomiej; Yoshida, Kenichi; Jerez, Andres; LaFramboise, Thomas; Polprasert, Chantana; Clemente, Michael J.; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Sanada, Masashi; Cui, Edward; Verma, Amit K.; McDevitt, Michael A.; List, Alan F.; Saunthararajah, Yogen; Sekeres, Mikkael A.; Boultwood, Jacqueline; Ogawa, Seishi; Maciejewski, Jaroslaw P.

In: Oncotarget, Vol. 8, No. 4, 2017, p. 6483-6495.

Research output: Contribution to journalArticle

Hosono, N, Makishima, H, Mahfouz, R, Przychodzen, B, Yoshida, K, Jerez, A, LaFramboise, T, Polprasert, C, Clemente, MJ, Shiraishi, Y, Chiba, K, Tanaka, H, Miyano, S, Sanada, M, Cui, E, Verma, AK, McDevitt, MA, List, AF, Saunthararajah, Y, Sekeres, MA, Boultwood, J, Ogawa, S & Maciejewski, JP 2017, 'Recurrent genetic defects on chromosome 5q in myeloid neoplasms', Oncotarget, vol. 8, no. 4, pp. 6483-6495. https://doi.org/10.18632/oncotarget.14130
Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A et al. Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget. 2017;8(4):6483-6495. https://doi.org/10.18632/oncotarget.14130
Hosono, Naoko ; Makishima, Hideki ; Mahfouz, Reda ; Przychodzen, Bartlomiej ; Yoshida, Kenichi ; Jerez, Andres ; LaFramboise, Thomas ; Polprasert, Chantana ; Clemente, Michael J. ; Shiraishi, Yuichi ; Chiba, Kenichi ; Tanaka, Hiroko ; Miyano, Satoru ; Sanada, Masashi ; Cui, Edward ; Verma, Amit K. ; McDevitt, Michael A. ; List, Alan F. ; Saunthararajah, Yogen ; Sekeres, Mikkael A. ; Boultwood, Jacqueline ; Ogawa, Seishi ; Maciejewski, Jaroslaw P. / Recurrent genetic defects on chromosome 5q in myeloid neoplasms. In: Oncotarget. 2017 ; Vol. 8, No. 4. pp. 6483-6495.
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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.

PY - 2017

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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.

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