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

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.

Elevated serum γ-glutamyl transferase is associated with low muscle function in adults independent of muscle mass.

OBJECTIVE: Elevated serum γ-glutamyl transferase (GGT), a hepatic cholestasis or liver damage marker, has been associated with low lean mass and adiposity. However, whether serum GGT can predict muscle function in adults remains unclear. The aim of this study was to determine whether an elevated serum GGT is associated with low peak weight-corrected jump power (JP) and low handgrip strength (HGS). METHODS: This study included 662 individuals aged ≥50 y in the final cohort (women, 86%; mean age, 64.8 y). The primary outcome was low peak weight-corrected JP defined as <23.8 W/kg and <19W/kg in men and women, respectively, and the secondary outcome was low HGS (<28 kg in men; <18 kg in women). RESULTS: Participants with low JP had a higher GGT level, older age, lower HGS, and higher body fat than those without low JP. Serum GGT showed a negative association with JP (adjusted ß = -1.16, P = 0.005) and HGS (adjusted ß = -0.92, P = 0.018). One log-unit increment in GGT was associated with elevated odds of low JP (adjusted odds ratio [aOR] 2.13, P = 0.002) after adjustment for age, sex, lean mass, and body fat percentage, particularly in individuals without hepatic steatosis (aOR, 2.30) versus those with hepatic steatosis (aOR, 0.80; Pinteraction = 0.020). CONCLUSION: Elevated serum GGT was associated with low muscle function in adults independent of age, muscle mass, and adiposity, indicating that serum GGT may play a role as an independent marker of muscle function. .