The molecular landscape of well differentiated retroperitoneal liposarcoma

Robert Tyler; Mark P Dilworth; Jonathan James; Daniel Blakeway; Joanne D Stockton; Dion G Morton; Phillipe Taniere; David Gourevitch; Anant Desai; Andrew D Beggs

doi:10.1002/path.5749

The molecular landscape of well differentiated retroperitoneal liposarcoma

Robert Tyler, Mark P Dilworth, Jonathan James, Daniel Blakeway, Joanne D Stockton, Dion G Morton, Phillipe Taniere, David Gourevitch, Anant Desai, Andrew D Beggs

Cancer and Genomic Sciences

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Abstract

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Original language	English
Pages (from-to)	132-140
Number of pages	9
Journal	Journal of Pathology
Volume	255
Issue number	2
Early online date	22 Jun 2021
DOIs	https://doi.org/10.1002/path.5749
Publication status	Published - Oct 2021

Bibliographical note

Funding Information:
We thank Illumina UK (Miao He, Sean Humphray, Mahesh Vasipalli, Zoya Kingsbury, and David Bentley) for sequencing and bioinformatics support for this project. This work was partially funded by a pump priming grant from the Cancer Research UK Birmingham Experimental Cancer Medicine Centre. AB acknowledges funding from the Wellcome Trust (102732/Z/13/Z), Cancer Research UK (C31641/A23923), and the Medical Research Council (MR/M016587/1).

Publisher Copyright:
© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Keywords

RNA sequencing
liposarcoma
methylation
whole genome sequencing

ASJC Scopus subject areas

Pathology and Forensic Medicine

Access to Document

10.1002/path.5749Licence: Creative Commons: Attribution (CC BY)

path.5749Final published version, 2.86 MBLicence: Creative Commons: Attribution (CC BY)

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The molecular landscape of well differentiated retroperitoneal liposarcoma
Tyler, R., Dilworth, M., James, J., Blakeway, D., Stockton, J., Morton, D., Taniere, P., Gourevitch, D., Desai, A. & Beggs, A. D., 4 Jan 2021, MDPI, 34 p.
Research output: Working paper/Preprint › Preprint

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3 Finished

Understanding the molecular basis and consequences of chemoradiosensitivity in rectal cancer in order to improve tharapy (MOL-RSRC)
Middleton, G. (Co-Investigator), Cazier, J.-B. (Co-Investigator) & Beggs, A. (Principal Investigator)
Cancer Research Uk
3/04/17 → 31/03/22
Project: Research
Stratification in colorectal cancer: from Biology to Treatment Prediction (S-CORT)
Cazier, J.-B. (Co-Investigator), Morton, D. (Co-Investigator), Bach, S. (Co-Investigator) & Beggs, A. (Principal Investigator)
Medical Research Council
1/04/15 → 31/03/20
Project: Research Councils
Molecular Stratification of Rectal Cancer
Beggs, A. (Principal Investigator)
Wellcome Trust
3/02/14 → 30/04/17
Project: Research

Cite this

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title = "The molecular landscape of well differentiated retroperitoneal liposarcoma",

abstract = "Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. {\textcopyright} 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.",

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note = "Funding Information: We thank Illumina UK (Miao He, Sean Humphray, Mahesh Vasipalli, Zoya Kingsbury, and David Bentley) for sequencing and bioinformatics support for this project. This work was partially funded by a pump priming grant from the Cancer Research UK Birmingham Experimental Cancer Medicine Centre. AB acknowledges funding from the Wellcome Trust (102732/Z/13/Z), Cancer Research UK (C31641/A23923), and the Medical Research Council (MR/M016587/1). Publisher Copyright: {\textcopyright} 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.",

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AU - Gourevitch, David

AU - Desai, Anant

AU - Beggs, Andrew D

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IS - 2

ER -

The molecular landscape of well differentiated retroperitoneal liposarcoma

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Research output

The molecular landscape of well differentiated retroperitoneal liposarcoma

Projects

Understanding the molecular basis and consequences of chemoradiosensitivity in rectal cancer in order to improve tharapy (MOL-RSRC)

Stratification in colorectal cancer: from Biology to Treatment Prediction (S-CORT)

Molecular Stratification of Rectal Cancer

Cite this