Albrecht Stenzinger

CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer

Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. While copy number alteration-based scores such as HRDsum = LST + TAI + LOH are included in therapy approvals, single base substitutions (SBS) are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by alterations in BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C > T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC = 0.84, AUC = 0.85, and AUC = 0.88). The cutpoint fdeam = 13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity = 89% and specificity = 77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum in tumors of purity 40%, 20%, and 10%. Overcoming the limited robustness against low tumor purity, the new biomarker can contribute to a more sensitive detection of HRD in clinical samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies.

Expanding the molecular spectrum of gene fusions in endometrial stromal sarcoma: Novel subunits of the chromatin remodeling complexes PRC2 and NuA4/TIP60 as alternative fusion partners

AbstractEndometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1‐fusion positive ESS presented in a 58‐year‐old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid‐to‐epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27–62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow‐up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow‐up. The EPC1::EZH2‐fusion positive ESS presented in a 52‐year‐old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1‐related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low‐grade and high‐grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.