Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements

Jan B. Egan, Michael Barrett, Mia D. Champion, Sumit Middha, Elizabeth Lenkiewicz, Lisa Evers, Princy Francis, Jessica Schmidt, Chang Xin Shi, Scott Van Wier, Sandra Badar, Gregory Ahmann, K. Martin Kortuem, Nicole J. Boczek, Rafael Fonseca, David W. Craig, John D. Carpten, Mitesh J Borad, Alexander Keith Stewart

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.

Original languageEnglish (US)
Article numbere87113
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 5 2014

Fingerprint

Liposarcoma
gene fusion
Genes
aneuploidy
Genome
chromosomes
neoplasms
genome
comparative genomic hybridization
genomics
Chromosomes, Human, Pair 12
Chromosomes
Gene Fusion
retrotransposons
sarcoma
Aneuploidy
multigene family
Tumors
Fusion reactions
flow cytometry

ASJC Scopus subject areas

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

Cite this

Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements. / Egan, Jan B.; Barrett, Michael; Champion, Mia D.; Middha, Sumit; Lenkiewicz, Elizabeth; Evers, Lisa; Francis, Princy; Schmidt, Jessica; Shi, Chang Xin; Van Wier, Scott; Badar, Sandra; Ahmann, Gregory; Kortuem, K. Martin; Boczek, Nicole J.; Fonseca, Rafael; Craig, David W.; Carpten, John D.; Borad, Mitesh J; Stewart, Alexander Keith.

In: PLoS One, Vol. 9, No. 2, e87113, 05.02.2014.

Research output: Contribution to journalArticle

Egan, JB, Barrett, M, Champion, MD, Middha, S, Lenkiewicz, E, Evers, L, Francis, P, Schmidt, J, Shi, CX, Van Wier, S, Badar, S, Ahmann, G, Kortuem, KM, Boczek, NJ, Fonseca, R, Craig, DW, Carpten, JD, Borad, MJ & Stewart, AK 2014, 'Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements', PLoS One, vol. 9, no. 2, e87113. https://doi.org/10.1371/journal.pone.0087113
Egan, Jan B. ; Barrett, Michael ; Champion, Mia D. ; Middha, Sumit ; Lenkiewicz, Elizabeth ; Evers, Lisa ; Francis, Princy ; Schmidt, Jessica ; Shi, Chang Xin ; Van Wier, Scott ; Badar, Sandra ; Ahmann, Gregory ; Kortuem, K. Martin ; Boczek, Nicole J. ; Fonseca, Rafael ; Craig, David W. ; Carpten, John D. ; Borad, Mitesh J ; Stewart, Alexander Keith. / Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements. In: PLoS One. 2014 ; Vol. 9, No. 2.
@article{7c52356a58c64974914e163670cb675e,
title = "Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements",
abstract = "Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.",
author = "Egan, {Jan B.} and Michael Barrett and Champion, {Mia D.} and Sumit Middha and Elizabeth Lenkiewicz and Lisa Evers and Princy Francis and Jessica Schmidt and Shi, {Chang Xin} and {Van Wier}, Scott and Sandra Badar and Gregory Ahmann and Kortuem, {K. Martin} and Boczek, {Nicole J.} and Rafael Fonseca and Craig, {David W.} and Carpten, {John D.} and Borad, {Mitesh J} and Stewart, {Alexander Keith}",
year = "2014",
month = "2",
day = "5",
doi = "10.1371/journal.pone.0087113",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements

AU - Egan, Jan B.

AU - Barrett, Michael

AU - Champion, Mia D.

AU - Middha, Sumit

AU - Lenkiewicz, Elizabeth

AU - Evers, Lisa

AU - Francis, Princy

AU - Schmidt, Jessica

AU - Shi, Chang Xin

AU - Van Wier, Scott

AU - Badar, Sandra

AU - Ahmann, Gregory

AU - Kortuem, K. Martin

AU - Boczek, Nicole J.

AU - Fonseca, Rafael

AU - Craig, David W.

AU - Carpten, John D.

AU - Borad, Mitesh J

AU - Stewart, Alexander Keith

PY - 2014/2/5

Y1 - 2014/2/5

N2 - Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.

AB - Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.

UR - http://www.scopus.com/inward/record.url?scp=84895560276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895560276&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0087113

DO - 10.1371/journal.pone.0087113

M3 - Article

C2 - 24505276

AN - SCOPUS:84895560276

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e87113

ER -