Oncotarget

Research Papers:

Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor

Somayyeh Fahiminiya, Leora Witkowski, Javad Nadaf, Jian Carrot-Zhang, Catherine Goudie, Martin Hasselblatt, Pascal Johann, Marcel Kool, Ryan S. Lee, Tenzin Gayden, Charles W. M. Roberts, Jaclyn A. Biegel, Nada Jabado, Jacek Majewski and William D. Foulkes _

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Oncotarget. 2016; 7:1732-1740. https://doi.org/10.18632/oncotarget.6459

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Abstract

Somayyeh Fahiminiya1,2,*, Leora Witkowski1,*, Javad Nadaf1,2,*, Jian Carrot-Zhang1,2, Catherine Goudie3, Martin Hasselblatt4, Pascal Johann5, Marcel Kool6,7, Ryan S. Lee8, Tenzin Gayden1,3, Charles W. M. Roberts8,12, Jaclyn A. Biegel9, Nada Jabado1,3, Jacek Majewski1,2 and William D. Foulkes1,10,11

1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada

2 McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada

3 Department of Pediatrics, McGill University, Montreal, Quebec, Canada

4 Institute of Neuropathology, University Hospital Münster, Münster, Germany

5 Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany

6 Division of Pediatric Neuro-Oncology, German Cancer Research Center DKFZ, Heidelberg, Germany

7 German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany

8 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

9 Department of Pediatrics, Keck School of Medicine of USC, Los Angeles, California, USA

10 Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

11 Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada

12 Current affiliation: Comprehensive Cancer Center and Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

* These authors should be considered as joint first authors

Correspondence to:

William Foulkes, email:

Keywords: SCCOHT, ATRT, exome sequencing, SWI/SNF, methylation

Received: September 09, 2015 Accepted: November 16, 2015 Published: December 04, 2015

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy diagnosed in women under age 40. We and others recently determined that germline and/or somatic deleterious mutations in SMARCA4 characterize SCCOHT. Alterations in this gene, or the related SWI/SNF chromatin remodeling gene SMARCB1, have been previously reported in atypical teratoid/rhabdoid tumors (ATRTs) and malignant rhabdoid tumors (MRTs). To further describe the somatic landscape of SCCOHT, we performed whole exome sequencing on 14 tumors and their matched normal tissues and compared their genomic alterations with those in ATRT and ovarian high grade serous carcinoma (HGSC). We confirmed that SMARCA4 is the only recurrently mutated gene in SCCOHT, and show that recurrent allelic imbalance is observed exclusively on chromosome 19p, where SMARCA4 resides. By comparing genomic alterations between SCCOHT, ATRT and HGSC, we demonstrate that SCCOHTs, like ATRTs, have a remarkably simple genome and harbor significantly fewer somatic protein-coding mutations and chromosomal alterations than HGSC. Furthermore, a comparison of global DNA methylation profiles of 45 SCCOHTs, 65 ATRTs, and 92 HGSCs demonstrates a strong epigenetic correlation between SCCOHT and ATRT. Our results further confirm that the genomic and epigenomic signatures of SCCOHT are more similar to those of ATRT than HGSC, supporting our previous hypothesis that SCCOHT is a rhabdoid tumor and should be renamed MRT of the ovary. Furthermore, we conclude that SMARCA4 inactivation is the main cause of SCCOHT, and that new distinct therapeutic approaches should be developed to specifically target this devastating tumor.


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