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

Authors

Michael S Nakazawa
Ian M Silverman
Victoria Rimkunas
Artur Veloso
Dominik Glodzik
Adrienne Johnson
Toshiro K Ohsumi
Shreyaskumar R Patel
Anthony P Conley
Christina L Roland
Pamela T Soliman
Hannah C Beird
Chia-Chin Wu
Davis R Ingram
Rossana Lazcano
Dawon Song
Khalida M Wani
Alexander J Lazar
Timothy A Yap
Wei-Lien Wang
J Andrew Livingston

Publication Date

7-2-2024

Journal

Molecular Cancer Therapeutics

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.

Keywords

Humans, Ribonuclease H, Leiomyosarcoma, Female, DNA Repair, Biomarkers, Tumor, Male, Prognosis, Middle Aged, Aged, DNA Damage

DOI

10.1158/1535-7163.MCT-23-0761

PMID

38561019

PMCID

PMC11321279

PubMedCentral® Posted Date

1-2-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes