Genomic landscape of endometrial stromal sarcoma of uterus

// Youn Jin Choi 1, * Seung-Hyun Jung 2, 3, * Min Sung Kim 1 , In-Pyo Baek 2, 3 , Jae-Keun Rhee 4 , Sung Hak Lee 5 , Soo Young Hur 7 , Tae-Min Kim 4 , Yeun-Jun Chung 2, 3, 6 , Sug Hyung Lee 1, 2 1 Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 2 Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 3 Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 4 Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 5 Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 6 Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea 7 Department of Obstetrics/Gynecology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea * These authors have contributed equally to this work Correspondence to: Yeun-Jun Chung, e-mail: yejun@catholic.ac.kr Sug Hyung Lee, e-mail: suhulee@catholic.ac.kr Keywords: endometrial stromal sarcoma, mutation, genome, whole exome, copy number Received: July 07, 2015 Accepted: September 18, 2015 Published: September 30, 2015 ABSTRACT Although recurrent gene fusions such as JAZF1-JJAZ1 are considered driver events for endometrial stromal sarcoma (ESS) development, other genomic alterations remain largely unknown. In this study, we performed whole-exome sequencing, transcriptome sequencing and copy number profiling for five ESSs (three low-grade ESS (LG-ESS) and two undifferentiated uterine sarcomas (UUSs)). All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not. All ESSs except one LG-ESS exhibited copy number alterations (CNAs), many of which encompassed cancer-related genes. In UUSs, five CNAs encompassing cancer-related genes ( EZR, CDH1, RB1, TP53 and PRKAR1A ) accompanied their expressional changes, suggesting that they might stimulate UUS development. We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations. However, they were non-recurrent and did not include any well-known mutations, indicating that point mutations may not be a major driver for ESS development. Our data show that gene fusions and CNAs are the principal drivers for LG-ESS and USS, respectively, but both may require additional genomic alterations including point mutations. These differences may explain the different biologic behaviors between LG-ESS and UUS. Our findings suggest that ESS development requires point mutations and CNAs as well as the gene fusions.