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

Autor:	Nakazawa MS; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Silverman IM; Repare Therapeutics, Cambridge, Massachusetts., Rimkunas V; Repare Therapeutics, Cambridge, Massachusetts., Veloso A; Repare Therapeutics, Cambridge, Massachusetts., Glodzik D; Repare Therapeutics, Cambridge, Massachusetts., Johnson A; Repare Therapeutics, Cambridge, Massachusetts., Ohsumi TK; Repare Therapeutics, Cambridge, Massachusetts., Patel SR; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Conley AP; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Roland CL; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Soliman PT; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Beird HC; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wu CC; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ingram DR; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lazcano R; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Song D; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wani KM; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lazar AJ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Yap TA; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang WL; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Livingston JA; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Jul 02; Vol. 23 (7), pp. 1057-1065.
DOI:	10.1158/1535-7163.MCT-23-0761
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu