Non-gestational choriocarcinoma with hyperprogression on pembrolizumab: A case report and review of the literature.

Non-gestational choriocarcinoma is a rare and aggressive germ cell tumor. Here we present the case of a post-menopausal 49-year-old woman who presented with metastatic disease and initially achieved a complete radiographic and biomarker response with seven cycles of EMA-CO chemotherapy. Upon recurrence, she received two separate courses of chemotherapy, initially with paclitaxel/cisplatin/etoposide and later FOLFOX. Tumor analysis revealed 22% PD-L1 positivity (tumor proportion score) and she was treated with pembrolizumab. However, ßhCG levels rose abruptly and uncharacteristically through all three cycles of anti-PD1 therapy. The patient developed dyspnea on exertion, cough, and right flank pain. CT imaging demonstrated marked progression of liver metastases and innumerable new pulmonary metastases and the patient died 10 weeks after starting pembrolizumab. Here we describe the clinical presentation and management of this patient, along with analysis of molecular aberrations which could potentially explain hyperprogression in response to pembrolizumab.

ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer.

Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that BRCA1 is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote BRCA1 transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces BRCA1 promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors, ZC3H18 and E2F4 mRNA levels are positively correlated with BRCA1 mRNA levels, further supporting ZC3H18 role in regulating BRCA1. Given that ZC3H18 lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that ZC3H18 copy number losses could contribute to HR defects in HGSOC.