Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer.

BACKGROUND: The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous. METHODS: In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs. RESULTS: In a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs. CONCLUSIONS: These data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes.

A case of checkpoint inhibitor-induced celiac disease.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have now become standard of care treatment for many malignancies. ICIs are associated with unique immune mediated adverse events (irAEs) due to dysregulation of immune activation. As treatment with ICIs is becoming more common, rare irAEs are also being recognized. Here we report a case of ICI-induced celiac disease. CASE: A 74-year-old Caucasian female with metastatic renal carcinoma received second line nivolumab (anti-PD1 antibody) after initial disease progression on sunitinib. Ipilimumab was added after she failed to respond to six cycles of nivolumab monotherapy. One week after her first cycle of combination treatment, she presented with nausea, vomiting, grade 1 diarrhea, and weight loss. She underwent endoscopy, which showed bile stasis in the stomach, normal appearing stomach mucosa, and nonbleeding erythematous mucosa in the duodenal bulb. Stomach biopsy showed moderate active chronic gastritis. Duodenal biopsy showed moderate chronic active duodenitis with focal neutrophilic cryptitis, mucosal erosions, villous atrophy, mildly increased intraepithelial lymphocytes, and moderate chronic inflammation in the lamina propria pathognomonic of celiac disease. Symptoms improved with gluten-free diet, twice-daily omeprazole and anti-emetics and she was able to continue on treatment. CONCLUSIONS: There has been only one published case reporting ICI-induced celiac disease. Our case report highlights a rare irAE (celiac disease) associated with ICI treatment. It is unclear whether the patient had previously undiagnosed celiac disease or whether ICIs triggered her enteritis. Our patient was able to continue treatment with ICIs with dietary modifications, suggesting correct diagnosis is critical for optimal patient outcome.

Immune checkpoint inhibitor-induced colitis: A comprehensive review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target down-regulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1. ICIs have revolutionized the treatment of a variety of malignancies. However, many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis (IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease, however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.

Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.

BACKGROUND: Immune-mediated diarrhea and colitis (IMDC) can limit immune checkpoint inhibitors (ICIs) treatment, which is efficacious for advanced malignancies. Steroids and infliximab are commonly used to treat it. These agents induce systemic immunosuppression, with its associated morbidity. We assessed clinical outcomes of vedolizumab as an alternative treatment for IMDC. METHODS: We analyzed a retrospective case series of adults who had IMDC refractory to steroids and/or infliximab and received vedolizumab from 12/2016 through 04/2018. RESULTS: Twenty-eight patients were included. The median time from ICI therapy to IMDC onset was 10 weeks. Fifteen patients (54%) had grade 2 and 13 (46%) had grade 3 or 4 IMDC. Mucosal ulceration was present in 8 patients (29%), and nonulcerative inflammation was present in 13 (46%). All patients had features of active histologic inflammation; 14 (50%) had features of chronicity, and 10 (36%) had features of microscopic colitis concurrently. The mean duration of steroid therapy was 96 days (standard deviation 74 days). Nine patients received infliximab in addition to steroids and their IMDC was refractory to it. Among these, the duration of steroid use was 131 days compared with 85 days in patients who did not receive infliximab. Likewise, patients who failed infliximab before vedolizumab had a clinical success rate of 67% compared to 95% for patients that did not receive infliximab. The median number of vedolizumab infusions was 3 (interquartile range 1-4). The mean duration of follow-up was 15 months. Twenty-four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially; 5/17 patients (29%) reached histologic remission as well. CONCLUSIONS: Vedolizumab can be appropriate for the treatment of steroid-refractory IMDC, with favorable outcomes and a good safety profile.