Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas

Author:

Nakazawa Michael S.1ORCID,Silverman Ian M.2ORCID,Rimkunas Victoria2ORCID,Veloso Artur2ORCID,Glodzik Dominik2ORCID,Johnson Adrienne2ORCID,Ohsumi Toshiro K.2ORCID,Patel Shreyaskumar R.1ORCID,Conley Anthony P.1ORCID,Roland Christina L.3ORCID,Soliman Pamela T.4ORCID,Beird Hannah C.5ORCID,Wu Chia-Chin5ORCID,Ingram Davis R.6ORCID,Lazcano Rossana6ORCID,Song Dawon6ORCID,Wani Khalida M.6ORCID,Lazar Alexander J.56ORCID,Yap Timothy A.7ORCID,Wang Wei-Lien8ORCID,Livingston J. Andrew1ORCID

Affiliation:

1. Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 1

2. Repare Therapeutics, Cambridge, Massachusetts. 2

3. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3

4. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4

5. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5

6. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6

7. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7

8. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8

Abstract

Abstract Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

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