Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis

Timothy A. Graubert, Michelle A. Payton, Jin Shao, Richard A. Walgren, Ryan S. Monahan, John L. Frater, Mark A. Walshauser, Michael Martin, Yumi Kasai, Matthew J. Walter

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.

Original languageEnglish (US)
Article numbere4583
JournalPloS one
Volume4
Issue number2
DOIs
StatePublished - Feb 25 2009

Fingerprint

Haploinsufficiency
Myelodysplastic Syndromes
Chromosomes
pathogenesis
Genes
chromosomes
genomics
genes
comparative genomic hybridization
Comparative Genomic Hybridization
Nucleotides
nucleotides
chromosome elimination
sampling
Chromosome Deletion
chromosome aberrations
Sequence Deletion
point mutation
Polymorphism
cytogenetics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Graubert, T. A., Payton, M. A., Shao, J., Walgren, R. A., Monahan, R. S., Frater, J. L., ... Walter, M. J. (2009). Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. PloS one, 4(2), [e4583]. https://doi.org/10.1371/journal.pone.0004583

Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. / Graubert, Timothy A.; Payton, Michelle A.; Shao, Jin; Walgren, Richard A.; Monahan, Ryan S.; Frater, John L.; Walshauser, Mark A.; Martin, Michael; Kasai, Yumi; Walter, Matthew J.

In: PloS one, Vol. 4, No. 2, e4583, 25.02.2009.

Research output: Contribution to journalArticle

Graubert, TA, Payton, MA, Shao, J, Walgren, RA, Monahan, RS, Frater, JL, Walshauser, MA, Martin, M, Kasai, Y & Walter, MJ 2009, 'Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis', PloS one, vol. 4, no. 2, e4583. https://doi.org/10.1371/journal.pone.0004583
Graubert, Timothy A. ; Payton, Michelle A. ; Shao, Jin ; Walgren, Richard A. ; Monahan, Ryan S. ; Frater, John L. ; Walshauser, Mark A. ; Martin, Michael ; Kasai, Yumi ; Walter, Matthew J. / Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. In: PloS one. 2009 ; Vol. 4, No. 2.
@article{0863d828ac31431e81a96cfd3136acb8,
title = "Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis",
abstract = "Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50{\%} in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.",
author = "Graubert, {Timothy A.} and Payton, {Michelle A.} and Jin Shao and Walgren, {Richard A.} and Monahan, {Ryan S.} and Frater, {John L.} and Walshauser, {Mark A.} and Michael Martin and Yumi Kasai and Walter, {Matthew J.}",
year = "2009",
month = "2",
day = "25",
doi = "10.1371/journal.pone.0004583",
language = "English (US)",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis

AU - Graubert, Timothy A.

AU - Payton, Michelle A.

AU - Shao, Jin

AU - Walgren, Richard A.

AU - Monahan, Ryan S.

AU - Frater, John L.

AU - Walshauser, Mark A.

AU - Martin, Michael

AU - Kasai, Yumi

AU - Walter, Matthew J.

PY - 2009/2/25

Y1 - 2009/2/25

N2 - Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.

AB - Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.

UR - http://www.scopus.com/inward/record.url?scp=84887212500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887212500&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0004583

DO - 10.1371/journal.pone.0004583

M3 - Article

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e4583

ER -