Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type
Por:
Karnezis, AN, Wang, YM, Ramos, P, Hendricks, WPD, Oliva, E, D'Angelo, E, Prat, J, Nucci, MR, Nielsen, TO, Chow, C, Leung, S, Kommoss, F, Kommoss, S, Silva, A, Ronnett, BM, Rabban, JT, Bowtell, DD, Weissman, BE, Trent, JM, Gilks, CB, Huntsman, DG
Publicada:
1 feb 2016
Resumen:
Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines. (c) 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Filiaciones:
Karnezis, AN:
Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
Wang, YM:
Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
Ramos, P:
Translat Genom Res Inst TGen, Div Integrated Canc Genom, Phoenix, AZ USA
Hendricks, WPD:
Translat Genom Res Inst TGen, Div Integrated Canc Genom, Phoenix, AZ USA
Oliva, E:
Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
D'Angelo, E:
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, Dept Pathol, Barcelona, Spain
Prat, J:
Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, Dept Pathol, Barcelona, Spain
Nucci, MR:
Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA
Nielsen, TO:
Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
Chow, C:
Univ British Columbia, Vancouver Gen Hosp, Genet Pathol Evaluat Ctr, Vancouver, BC V5Z 1M9, Canada
Leung, S:
Univ British Columbia, Vancouver Gen Hosp, Genet Pathol Evaluat Ctr, Vancouver, BC V5Z 1M9, Canada
Kommoss, F:
Synlab MVZ Pathol, Mannheim, Germany
Kommoss, S:
Univ Hosp Tuebingen, Dept Obstet & Gynecol, Tubingen, Germany
Silva, A:
Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA
Ronnett, BM:
Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA
Rabban, JT:
Univ Calif San Francisco, Dept Anat Pathol, San Francisco, CA 94143 USA
Bowtell, DD:
Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia
Weissman, BE:
Univ N Carolina, Dept Pathol & Lab Med, Lineberger Canc Ctr, Chapel Hill, NC USA
Trent, JM:
Translat Genom Res Inst TGen, Div Integrated Canc Genom, Phoenix, AZ USA
Gilks, CB:
Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
Huntsman, DG:
Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
Univ British Columbia, Vancouver Gen Hosp, Genet Pathol Evaluat Ctr, Vancouver, BC V5Z 1M9, Canada
British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada
Green Published, Hybrid Gold
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