IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity
A partir de 13 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer papillaire du sein présentant une polarité inversée des cellules tumorales, cette étude identifie la présence fréquente de mutations des gènes IDH2 et PIK3CA
Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which eight of ten displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype by identifying IDH2 and PIK3CA mutations that may help diagnose it and possibly direct effective treatment.