Abstract 138: Solid papillary carcinoma with reverse polarization are driven by IDH2 and PI3K pathway mutations

Background: Solid papillary carcinoma with reverse polarization (SPCRP) is a rare breast cancer subtype, whose most striking morphologic feature is the presence of back-to-back columnar epithelial cells with nuclei situated in an apical rather than in the normal basal location. We sought to characterize the morphologic and genetic landscape of SPCRP and determine whether it represents a distinct subtype of breast cancer underpinned by highly recurrent disease-specific genetic alterations. Material and Methods: Archival sections of 13 SPCRPs were subjected to microdissection. DNA samples extracted from microdissected tumor and matched normal samples were subjected to whole exome sequencing (n = 2) on an Illumina HiSeq2000, and DNA samples from tumors were further subjected to targeted massively parallel sequencing (n = 1), SNaPshot profiling (n = 7) and/or Sanger sequencing. State-of-the-art bioinformatics methods were used to define somatic mutations. Non-malignant breast epithelial MCF10A cells with and without somatic PIK3CA H1047R knock-in were used to assess the functional impact of the mutations identified by sequencing of SPCRPs in two- and three-dimensional cell culture systems. Results: Ten of 13 (77%) SPCRPs were found to harbor IDH2 R172 hotspot mutations, and eight of these cases had concurrent pathogenic mutations affecting PIK3CA or PIK3R1, in particular PIK3CA H1047R hotspot mutations. Functional monolayer and three-dimensional cell culture studies demonstrated that IDH2 R172 and PIK3CA mutations constitute likely drivers of this tumor and contribute to its unusual nuclear polarization phenotype. Conclusions: Our results suggest that SPCRP is a distinct subtype of breast cancer underpinned by IDH2 hotspot mutations in conjunction with mutations affecting canonical genes of the PI3K pathway. Given that IDH2 hotspot mutations have not been described in breast cancer to date, these may be used as a diagnostic ancillary marker for SPCRPs. Furthermore, IDH2 mutations may serve as a potential therapeutic target in SPCRP patients with disseminated disease. Citation Format: Sarah Chiang, Britta Weigelt, Huei-Chi Wen, Salvatore Piscuoglio, Luciano G. Martelotto, Charlotte K Y Ng, Jörg Balss, Gabrielle Baker, Kimberly S. Cole, Andreas von Deimling, Julie M. Batten, Jonathan D. Marotti, Hwei-Choo Soh, Benjamin L. McCalip, Raymond S. Lim, Kalliopi P. Siziopikou, Randi Burke, Song Lu, Xiaolong Liu, Tarek Hammour, Edi Brogi, A John Iafrate, Jorge S. Reis-F