Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Ronald L. Chandler, Jeffrey S. Damrauer, Jesse R. Raab, Jonathan C. Schisler, Matthew D. Wilkerson, John P. Didion, Joshua Starmer, Daniel Serber, Della Yee, Jessie Xiong, David B. Darr, Fernando Pardo-Manuel de Villena, William Y. Kim and Terry Magnuson ()
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Ronald L. Chandler: University of North Carolina at Chapel Hill
Jeffrey S. Damrauer: University of North Carolina at Chapel Hill
Jesse R. Raab: University of North Carolina at Chapel Hill
Jonathan C. Schisler: McAllister Heart Institute, University of North Carolina at Chapel Hill
Matthew D. Wilkerson: University of North Carolina at Chapel Hill
John P. Didion: University of North Carolina at Chapel Hill
Joshua Starmer: University of North Carolina at Chapel Hill
Daniel Serber: University of North Carolina at Chapel Hill
Della Yee: University of North Carolina at Chapel Hill
Jessie Xiong: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
David B. Darr: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Fernando Pardo-Manuel de Villena: University of North Carolina at Chapel Hill
William Y. Kim: University of North Carolina at Chapel Hill
Terry Magnuson: University of North Carolina at Chapel Hill

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis.

Date: 2015
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DOI: 10.1038/ncomms7118

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