Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.
In: Molecular cancer therapeutics, 2024-04-02
academicJournal
Zugriff:
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 tissue 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 to 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) vs Non-HomDel (n=37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNASEH2B 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.
Titel: |
Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.
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Autor/in / Beteiligte Person: | Nakazawa, MS ; Silverman, IM ; Rimkunas, V ; Veloso, A ; Glodzik, D ; Johnson, A ; Ohsumi, TK ; Patel, SR ; Conley, AP ; Roland, CL ; Soliman, PT ; Beird, HC ; Wu, CC ; Ingram, DR ; Lazcano, R ; Song, D ; Wani, KM ; Lazar, AJ ; Yap, TA ; Wang, WL ; Livingston, JA |
Zeitschrift: | Molecular cancer therapeutics, 2024-04-02 |
Veröffentlichung: | Ahead of Print, 2024 |
Medientyp: | academicJournal |
ISSN: | 1538-8514 (electronic) |
DOI: | 10.1158/1535-7163.MCT-23-0761 |
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