Chiang Sarah, Weigelt Britta, Wen Huei-Chi, Pareja Fresia, Raghavendra Ashwini, Martelotto Luciano G, Burke Kathleen A, Basili Thais, Li Anqi, Geyer Felipe C, Piscuoglio Salvatore, Ng Charlotte K Y, Jungbluth Achim A, Balss Jörg, Pusch Stefan, Baker Gabrielle M, Cole Kimberly S, von Deimling Andreas, Batten Julie M, Marotti Jonathan D, Soh Hwei-Choo, McCalip Benjamin L, Serrano Jonathan, Lim Raymond S, Siziopikou Kalliopi P, Lu Song, Liu Xiaolong, Hammour Tarek, Brogi Edi, Snuderl Matija, Iafrate A John, Reis-Filho Jorge S, Schnitt Stuart J
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Res. 2016 Dec 15;76(24):7118-7129. doi: 10.1158/0008-5472.CAN-16-0298. Epub 2016 Oct 20.
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 8 of 10 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 hotspot 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. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. Cancer Res; 76(24); 7118-29. ©2016 AACR.
具有反向极性的实性乳头状癌（SPCRP）是一种病因不明的罕见乳腺癌亚型。在本研究中，我们试图描述其独特的组织病理学特征，并使用大规模平行全外显子测序和靶向测序来鉴定构成SPCRP的基因改变。SPCRP的形态学和免疫组化特征支持该亚型的侵袭性。13例SPCRP中有10例（77%）在异柠檬酸脱氢酶IDH2的R172位点存在热点突变，其中10例中的8例同时存在影响PIK3CA或PIK3R1的致病性突变。1例IDH2野生型SPCRP存在TET2 Q548*截短突变并伴有PIK3CA H1047R热点突变。功能研究表明，IDH2和PIK3CA热点突变可能是SPCRP的驱动因素，导致其核极性反转表型。我们的结果为SPCRP作为一种独特的乳腺癌亚型提供了分子定义。IDH2和PIK3CA同时突变可能有助于诊断SPCRP并可能指导有效治疗。《癌症研究》；76(24)；7118 - 29。©2016美国癌症研究协会。
