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

Michael S Nakazawa1, Ian M Silverman2, Victoria Rimkunas2

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

Molecular Cancer Therapeutics
|April 1, 2024
PubMed

Insights

Loss of RNase H2 is common in uterine leiomyosarcoma (U-LMS) and may indicate actionable alterations for DNA damage response (DDR) targeted therapies. RNase H2 immunohistochemistry (IHC) shows promise as a predictive biomarker for U-LMS clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Targeting the DNA damage response (DDR) pathway is a promising therapeutic strategy for leiomyosarcoma (LMS).
  • RNase H2, a key member of the DDR pathway, represents a potential therapeutic target in LMS.
  • Loss of RNase H2 function is an actionable alteration for DDR-targeted treatments.

Purpose of the Study:

  • To develop and validate protein- and genomic-based assays to screen for RNase H2 loss in LMS.
  • To determine the prevalence and prognostic significance of RNase H2 deficiency in different subtypes of LMS.
  • To evaluate RNase H2 immunohistochemistry (IHC) as a predictive biomarker for DDR-targeted therapies in U-LMS.

Main Methods:

  • Utilized RNase H2-specific antibody on a pan-tumor tissue microarray (TMA) to assess protein expression across various tumor types, including LMS.
  • Analyzed RNase H2 deficiency in uterine LMS (U-LMS) and soft-tissue LMS (ST-LMS) cohorts.
  • Employed targeted next-generation sequencing (NGS) assay (SNiPDx) to detect biallelic loss of function (HomDels) in RNASEH2B.
  • Correlated RNase H2 protein levels with genomic alterations and clinical outcomes in U-LMS patients.

Main Results:

  • RNase H2 loss was significantly more frequent in LMS (11.5%) compared to other tumors (3.8%).
  • RNase H2 deficiency was confirmed in 21% of U-LMS and 30% of ST-LMS cases.
  • RNASEH2B homozygous deletions (HomDels) were identified in 6% of LMS cases in the TCGA database, with a higher prevalence in U-LMS (15%).
  • Targeted NGS detected RNASEH2B HomDels in 54% of U-LMS cases with RNase H2 loss by IHC.
  • RNase H2 loss or RNASEH2B HomDel status did not significantly impact overall survival in U-LMS patients.
  • RNase H2 IHC demonstrated 76% diagnostic accuracy, 93% sensitivity, and 71% specificity for detecting RNASEH2B HomDels in U-LMS.

Conclusions:

  • RNase H2 deficiency is a prevalent alteration in LMS, particularly in U-LMS.
  • RNase H2 IHC is a sensitive and specific method for detecting RNASEH2B HomDels in U-LMS.
  • RNase H2 IHC shows potential as a predictive biomarker for DDR-targeted clinical trials in U-LMS.
  • Further development of RNase H2 IHC is warranted for biomarker-driven clinical trials in U-LMS.

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