title: IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity.
abstract: 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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. chiangs@mskcc.org sschnitt@bidmc.harvard.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chiang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Huei-Chi
authors.initials: HC
authors.lastname: Wen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fresia
authors.initials: F
authors.lastname: Pareja
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Raghavendra
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Luciano G
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Burke
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Thais
authors.initials: T
authors.lastname: Basili
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anqi
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Balss
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Baker
authors.affiliation: Department of Pathology, University of Iowa Hospital and Clinics, Iowa City, Iowa.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Cole
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Batten
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Marotti
authors.affiliation: Pathology North, North Shore Private Hospital, New South Wales, Australia.
authors.forename: Hwei-Choo
authors.initials: HC
authors.lastname: Soh
authors.affiliation: Miami Valley Hospital, Dayton, Ohio.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: McCalip
authors.affiliation: Department of Pathology, New York University Langone Medical Center and Medical School, New York, New York.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Serrano
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Kalliopi P
authors.initials: KP
authors.lastname: Siziopikou
authors.affiliation: Department of Pathology, Mon General Hospital, Morgantown, West Virginia.
authors.forename: Song
authors.initials: S
authors.lastname: Lu
authors.affiliation: ABQ Health Partners, Albuquerque, New Mexico.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Maine Medical Center, Portland, Maine.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hammour
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Department of Pathology, New York University Langone Medical Center and Medical School, New York, New York.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.|Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts. chiangs@mskcc.org sschnitt@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D007521:Isocitrate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; C538784:IDH2 protein, human; C484760:PIK3CA protein, human