부산대학교 도서관

Keywords: liposarcoma; whole genome sequencing; RNA sequencing; methylation 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. Article Note: No conflicts of interest were declared. CAPTION(S): Figure S1. Bar chart of the frequency of mutations from whole genome sequencing data for genes taken from the Cancer Gene Census and from previous literature on liposarcoma Figure S2. Diagram of FOXD4L3 showing the Forkhead binding domain Figure S3. Ensemble reference diagram showing the expression of FOXD4L3 in normal adipose tissue via RNAseq and cDNA, and in pooled RNAseq data Figure S4. Circos plots of structural variation in four samples Figure S5. Structural rearrangement plots from whole genome sequencing data Figure S6. Methylation volcano plot of differentially expressed genes between liposarcoma and normal fat Table S1. Table of primers for targeting of exon 1 of FOXD4L3 Table S2. Table of mutation metrics for liposarcoma samples Table S3. Mutation spectra Table S4. Table of associations between FOXD4L3 and other genes from the STRINGS database Table S5. RNAseq data from tumour versus normal Table S6. Alternate splicing events from RNAseq data of tumour versus normal Table S7. CIBERSORT analysis for tumour RNAseq Table S8. Fusion calling from RNAseq Table S9. List of methylation variable positions comparing liposarcoma with normal Byline: Robert Tyler, Mark P Dilworth, Jonathan James, Daniel Blakeway, Joanne D Stockton, Dion G Morton, Phillipe Taniere, David Gourevitch, Anant Desai, Andrew D Beggs