Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease

Ana Cristina Vargas,Fiona M Maclean,Anthony J Gill,Elizabeth M Algar,Peter Russell,Alison L Cheah,Annabelle Mahar,Christine L White,Lesley-Ann Gray,Nima Mesbah Ardakani,Fiona Bonar,Peter Grimison

doi:10.1038/s41598-020-79648-6

Abstract

In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.

Highlights

In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genomewide methylation changes occur during metastatic and recurrent (Met/Rec) disease
A retrospective database search was performed in the archives of Douglass Hanly Moir (DHM) Pathology laboratory to identify FFPE tissue blocks derived from surgical resections of patients with selected sarcoma types (LMS, MFS, synovial sarcoma (SS) & RMS), who developed metastatic (Mets) and/or recurrent (Rec) tumours within a 5-year period and whose residual archival tumour blocks were adequate for further molecular analysis
In this study we performed for the first time, genome-wide methylation comparative analysis of matched selected sarcoma samples obtained at different time points during the evolution of the tumours

Summary

Introduction

In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genomewide methylation changes occur during metastatic and recurrent (Met/Rec) disease. In the only study available with comprehensive genomic (but no epigenomic) data on specific sub-types of matched metastatic/recurrent sarcomas, Hofvander et al.[24], demonstrated no major changes occurred at the genetic level during clonal evolution. In this study we sought to investigate in a limited number of FFPE sarcoma samples (n = 32) from 14 individuals (LMS: n = 7; MFS: n = 4; RMS: n = 2; and SS: n = 1) whether methylation changes at a genome-wide level arise in metastatic or recurrent disease.

Objectives

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Results

Conclusion