IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity

Sarah Chiang; Britta Weigelt; Huei Chi Wen; Fresia Pareja; Ashwini Raghavendra; Luciano G. Martelotto; Kathleen A. Burke; Thais Basili; Anqi Li; Felipe C. Geyer; Salvatore Piscuoglio; Charlotte K.Y. Ng; Achim A. Jungbluth; Jörg Balss; Stefan Pusch; Gabrielle M. Baker; Kimberly S. Cole; Andreas Von Deimling; Julie M. Batten; Jonathan D. Marotti; Hwei Choo Soh; Benjamin L. McCalip; Jonathan Serrano; Raymond S. Lim; Kalliopi P. Siziopikou; Song Lu; Xiaolong Liu; Tarek Hammour; Edi Brogi; Matija Snuderl; A. John Iafrate; Jorge S. Reis-Filho; Stuart J. Schnitt

doi:10.1158/0008-5472.CAN-16-0298

IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity

Sarah Chiang^*, Britta Weigelt, Huei Chi Wen, Fresia Pareja, Ashwini Raghavendra, Luciano G. Martelotto, Kathleen A. Burke, Thais Basili, Anqi Li, Felipe C. Geyer, Salvatore Piscuoglio, Charlotte K.Y. Ng, Achim A. Jungbluth, Jörg Balss, Stefan Pusch, Gabrielle M. Baker, Kimberly S. Cole, Andreas Von Deimling, Julie M. Batten, Jonathan D. MarottiHwei Choo Soh, Benjamin L. McCalip, Jonathan Serrano, Raymond S. Lim, Kalliopi P. Siziopikou, Song Lu, Xiaolong Liu, Tarek Hammour, Edi Brogi, Matija Snuderl, A. John Iafrate, Jorge S. Reis-Filho, Stuart J. Schnitt

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

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.

Original language	English (US)
Pages (from-to)	7118-7129
Number of pages	12
Journal	Cancer Research
Volume	76
Issue number	24
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-0298
State	Published - Dec 15 2016

Funding

S. Piscuoglio was funded in part by a Susan G. Komen Postdoctoral Fellowship Grant (PDF14298348). J.S. Reis-Filho is funded in part by BCRF, and M. Snuderl is supported by the Friedberg Charitable Foundation. S. Chiang, B. Weigelt, H.-C. Wen, F. Pareja, A. Raghavendra, L.G. Martelotto, K.A. Burke, T. Basili, A. Li, F.C. Geyer, S. Piscuoglio, C.K.Y. Ng, A.A. Jungbluth, R.S. Lim, E. Brogi, and J.S. Reis-Filho were funded in part by a NIH/NCI Cancer Center Support Grant (P30 CA008748). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

ASJC Scopus subject areas

Oncology
Cancer Research

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Chiang, S., Weigelt, B., Wen, H. C., Pareja, F., Raghavendra, A., Martelotto, L. G., Burke, K. A., Basili, T., Li, A., Geyer, F. C., Piscuoglio, S., Ng, C. K. Y., Jungbluth, A. A., Balss, J., Pusch, S., Baker, G. M., Cole, K. S., Von Deimling, A., Batten, J. M., ... Schnitt, S. J. (2016). IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity. Cancer Research, 76(24), 7118-7129. https://doi.org/10.1158/0008-5472.CAN-16-0298

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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.",

author = "Sarah Chiang and Britta Weigelt and Wen, {Huei Chi} and Fresia Pareja and Ashwini Raghavendra and Martelotto, {Luciano G.} and Burke, {Kathleen A.} and Thais Basili and Anqi Li and Geyer, {Felipe C.} and Salvatore Piscuoglio and Ng, {Charlotte K.Y.} and Jungbluth, {Achim A.} and J{\"o}rg Balss and Stefan Pusch and Baker, {Gabrielle M.} and Cole, {Kimberly S.} and {Von Deimling}, Andreas and Batten, {Julie M.} and Marotti, {Jonathan D.} and Soh, {Hwei Choo} and McCalip, {Benjamin L.} and Jonathan Serrano and Lim, {Raymond S.} and Siziopikou, {Kalliopi P.} and Song Lu and Xiaolong Liu and Tarek Hammour and Edi Brogi and Matija Snuderl and Iafrate, {A. John} and Reis-Filho, {Jorge S.} and Schnitt, {Stuart J.}",

note = "Publisher Copyright: {\textcopyright}2016 AACR.",

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doi = "10.1158/0008-5472.CAN-16-0298",

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Chiang, S, Weigelt, B, Wen, HC, Pareja, F, Raghavendra, A, Martelotto, LG, Burke, KA, Basili, T, Li, A, Geyer, FC, Piscuoglio, S, Ng, CKY, Jungbluth, AA, Balss, J, Pusch, S, Baker, GM, Cole, KS, Von Deimling, A, Batten, JM, Marotti, JD, Soh, HC, McCalip, BL, Serrano, J, Lim, RS, Siziopikou, KP, Lu, S, Liu, X, Hammour, T, Brogi, E, Snuderl, M, Iafrate, AJ, Reis-Filho, JS & Schnitt, SJ 2016, 'IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity', Cancer Research, vol. 76, no. 24, pp. 7118-7129. https://doi.org/10.1158/0008-5472.CAN-16-0298

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T1 - IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity

AU - Chiang, Sarah

AU - Weigelt, Britta

AU - Wen, Huei Chi

AU - Pareja, Fresia

AU - Raghavendra, Ashwini

AU - Martelotto, Luciano G.

AU - Burke, Kathleen A.

AU - Basili, Thais

AU - Li, Anqi

AU - Geyer, Felipe C.

AU - Piscuoglio, Salvatore

AU - Ng, Charlotte K.Y.

AU - Jungbluth, Achim A.

AU - Balss, Jörg

AU - Pusch, Stefan

AU - Baker, Gabrielle M.

AU - Cole, Kimberly S.

AU - Von Deimling, Andreas

AU - Batten, Julie M.

AU - Marotti, Jonathan D.

AU - Soh, Hwei Choo

AU - McCalip, Benjamin L.

AU - Serrano, Jonathan

AU - Lim, Raymond S.

AU - Siziopikou, Kalliopi P.

AU - Lu, Song

AU - Liu, Xiaolong

AU - Hammour, Tarek

AU - Brogi, Edi

AU - Snuderl, Matija

AU - Iafrate, A. John

AU - Reis-Filho, Jorge S.

AU - Schnitt, Stuart J.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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.

AB - 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.

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ER -

IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity

Abstract

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