Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductiveaged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.

These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

Aim Macrophage migration inhibitory factor (MIF) is a cytokine whose expression is elevated in endometriotic tissue from women with the disease but the functional role of this factor in the pathogenesis of the disease is uncertain. The objective of the current study was to examine the role of MIF in the pathogenesis of endometriosis. Method Experimental endometriosis was induced in mice and the ability of the MIF antagonist, ISO-1, to reduce endometriotic implant size was assessed. Results Administration of ISO-1 resulted in a significant reduction in implant size and vascularity (as assessed by Flk1 mRNA expression) which was not associated with an alteration in the reproductive cycle. Conclusion These data suggest that inhibition of MIF activity is associated with a significant reduction in endometriotic implant size and leads us to speculate that a similar approach of targeting MIF may prove useful in treating endometriosis in humans.

1501 Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]

No abstract