Abstract A1-27: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) beyond SMARCA4 mutations: A comprehensive genomic analysis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-11, Vol.75 (22_Supplement_1), p.A1-A1-27
• Main Authors: Auguste, Aurélie, Deloger, Marc, Cyrta, Joanna, Formal, Audrey Le, Richon, Catherine, Droin, Nathalie, Brunn, Beatrice, Caron, Olivier, Devouassoux, Mojgan, Lhomme, Catherine, Pautier, Patricia, Genestie, Catherine, Leary, Alexandra
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.TRANSCAGEN-A1-27

Background: Small cell ovarian carcinoma of the hypercalcemic type (SCCOHT) is an extremely rare and aggressive tumor that affects mainly young women (median age = 24 years). Prognosis is poor as most patients die within 2 years of diagnosis. Until recently, the literature describing the genomic profile of SCCOHT was scarce. In the last few months, four groups have now confirmed that SMARCA4 mutations are a frequent event in SCCOHT. Methods: We performed an integrated genomic analysis using WES, RNA-seq and CGH approaches to identify other recurrent genomic alteration and potential therapeutic targets. Candidate SNVs identified by WES were validated by Sanger and RNA-Seq. 8 frozen tumors were available, including 6 with matching normal control DNA. In addition 33 tumor samples were available as FFPE. Results: Despite their high grade and aggressive clinical course, SCCOHT tumors display genomic stability, low mutation load (0.53mut.Mb) and few SCNAs. However when present, genomic alterations were recurrent. Integrated WES and CGH analysis revealed a frequent and unusual 19p CN LOH (in 5 of 6 tumors). Although overall mutation rate was low, the mutations that did occur were novel and recurrent in 50%-80% of SCCOHT. In addition to SMARCA4 mutation (M+), we validated 10 novel recurrent M+ (including ABCA7, ANKRD24, CACTIN, EMR1, FBN3, FUT5, GRIN3B, KANK3, KRI1 and PLK5) in 50%-80% of tumors at high allelic frequencies (mean=0.87). Similarly, when present, amplifications were recurrent, common to a third of tumors: such as the mitochondrial redox enzymes (SHMT2, NDUFA4L2) or the transmembrane transporter LRP1 were amplified (Log2>2.3). No common fusion transcripts were identified. Since SCCOHT often display initial chemosensitivity, but rapid progressions, we investigated the differential genomic profiles of treatment naive versus chemotherapy treated tumors to uncover candidate resistance genes. The only alteration significantly enriched in post treatment tumors were M+ in the putative efflux pump, ABCA7. These M+ could not be identified even at low allele fractions in treatment naive tumors, but were identified in all 3 treated tumors with a mean allelic frequency of 0.83. In terms of therapeutic implications, modulating mitochondrial metabolism or targeting the membrane transporter LRP1 or the ABCA7 efflux pump could provide therapeutic venues in the future. However the most promising approaches for now may be targeting cell cycle checkpoint regulators or c