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A Systems Biology Approach to Identify Mechanism of Tumourigenesis Caused by Loss of SMARCB1 in Malignant Rhabdoid Tumors (BACR28)

Lookup NU author(s): Dr Martina Finetti, Alicia Del Carpio Pons, Ben Skalkoyannis, Matthew Selby, Amanda Smith, Dr Stephen Crosier, Professor Simon Bailey, Professor Steven Clifford, Dr Daniel Williamson

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Abstract

BackgroundMalignant Rhabdoid Tumours are caused by a biallelic inactivation of a single gene (SMARCB1) which encodes a core subunit of the hSWI/SNF chromatin remodeling complex. hSWI/SNF regulates hundreds of downstream genes/pathways. Despite knowing thatSMARCB1 mutation causes MRT no studies have systematically identified specific downstream pathways critical to tumourigenesis. Understanding these downstream effects is critical to identifying therapeutic targets that can improve the survival of MRT patients.MethodTo reveal the global transcriptional changes caused by SMARCB1 deletion, we performed RNA-seq and 450k-methylation analyses in MRT human primary malignancies (n>30) and in 4 MRT cell lines in which Lentivirus was used to re-express SMARCB1 (G401, A204, CHLA-266, STA-WT1). Moreover to understand the dynamics of chromatin binding/remodeling following SMARCB1 re-expression we performed ChIP-seq in functional models.ResultsWe show that primary MRTs present a unique expression/methylation profile which confirms that MRT broadly constitute a single tumor type, when compared with other paediatric tumours. However despite their common cause MRT can be can sub-grouped by location (i.e CNS or kidney). We observe that re-expression of SMARCB1 in MRT cell lines determines activation/inactivation of specific downstream pathways (IL-6/TGFbeta), genome-wide alterations in methylation and consequently gene expression. Loss of SMARCB1 also promotes expression of aberrant isoforms and novel transcripts and causes genome-wide changes in SWI/SNF binding.AcknowledgementsCCLG; LOVE OLIVER; NECCR; CHILDREN WITH CANCER UK; BRAIN TRUST; FAM. WARKConclusionOur transcriptome and methylome analysis in primary MRT and in functional models allow us to study in unprecedented detail the effect of SMARCB1 loss in MRTs. Through integration of our data using systems biology methods we have provided for the first time a genome-wide catalogue of SMARCB1 tumourigenic changes in both primary and functional models. We have isolated and validated critical genes/pathways and biological mechanisms which may ultimately be targetable therapeutically and will lead to better treatments for what is currently one of the most lethal paediatric cancers known.


Publication metadata

Author(s): Finetti M, Pons AD, Skalkoyannis B, Selby M, Smith A, Crosier S, Bailey S, Clifford S, Williamson D

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: 2014 NCRI Cancer Conference

Year of Conference: 2014

Print publication date: 02/11/2014

Online publication date: 02/11/2014

Publisher: National Cancer Research Institute (NCRI)

URL: http://conference.ncri.org.uk/abstracts/2014/abstracts/BACR28.html

Sponsor(s): CCLG; LOVE OLIVER; NECCR; CHILDREN WITH CANCER UK; BRAIN TRUST; FAM. WARK


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