3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma.

person Sarah Chiang Memorial Sloan Kettering Cancer Center, New York, NY info_outline Sarah Chiang, Martee Leigh Hensley, Varshini Vasudevaraja, Ivy Tran, Yiying Yang, Colin JR Stewart, Kay J Park, Lora H Ellenson, Kristin Sikkink, Anthony Schmitt, Matija Snuderl

Authors person Sarah Chiang Memorial Sloan Kettering Cancer Center, New York, NY info_outline Sarah Chiang, Martee Leigh Hensley, Varshini Vasudevaraja, Ivy Tran, Yiying Yang, Colin JR Stewart, Kay J Park, Lora H Ellenson, Kristin Sikkink, Anthony Schmitt, Matija Snuderl Organizations Memorial Sloan Kettering Cancer Center, New York, NY, NYU Langone Health, New York, NY, King Edward Memorial Hospital, Perth, Australia, Arima Genomics, San Diego, CA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Arima Genomics, U.S. National Institutes of Health, NYU Langone Health Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomics datasets has recently been shown to detect large complex structural variants (SV) and chromatin architecture in normal and diseased human tissues. We applied genome-wide chromosome conformation capture (Hi-C) techniques in a variety of uterine sarcomas to identify novel therapeutic targets. Methods: Formalin-fixed paraffin-embedded tissue from 48 primary or recurrent uterine sarcomas were subjected to Hi-C to identify chromosomal rearrangements. The cohort included leiomyosarcoma (LMS, n = 7), adenosarcoma (AS, n = 7), endometrial stromal sarcoma (n = 7; high grade (HGESS), n = 4; low grade (LGESS), n = 3), sarcoma not otherwise specified (n = 17; high grade (HGNOS), n = 10, low grade (LGNOS), n = 7), undifferentiated uterine sarcoma (UUS, n = 6) and heterologous sarcoma (n = 2). Tumors were previously subjected to targeted DNA (n = 10) and/or RNA (n = 26) NGS with no therapeutic targets identified and only BCOR internal tandem duplication detected in a HGESS. Results: Hi-C detected SV in 73% of uterine sarcomas (n = 35/48), including those previously negative by targeted RNA NGS (n = 25/26). Homologous recombination repair (HRR) gene alterations were detected by Hi-C in 42% of tumors (n = 20/48), including AS (n = 5/7), HGESS (n = 2/4), LGESS (n = 1/3), LMS (n = 2/7), UUS (n = 2/6), heterologous sarcoma (n = 1/2), HGNOS (n = 3/10) and LGNOS (n = 1/7). SV included gene (gene to gene, n = 3; gene to non-coding DNA, n = 8) and proximity (n = 13) fusions disrupting HRR genes ( ATM , BRIP1 , CDK12 , CHEK1 , CHEK2 , NBN , PARP3 , RAD51B , RAD51C , RAD51D ) with enrichment for RAD51B fusions (50%, n = 10/20). Among all tumors with HRR gene alterations detected by Hi-C, only one uterine sarcoma harbored a missense ATM mutation by targeted DNA NGS (n = 1/5). Conclusions: Molecular characterization of uterine sarcomas by Hi-C may uncover HRR gene alterations not currently detectable by targeted DNA and RNA NGS. Homologous recombination deficiency (HRD) is not limited to LMS and may frequently result from SV, particularly between HRR gene to non-coding DNA in a variety of uterine sarcomas. These alternate mechanisms for HRD may serve as a potential therapeutic biomarker for HRD-targeted therapy in uterine sarcoma.

Pre-clinical