ABSTRACT
BACKGROUND: The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria. METHODS: From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks. Demographics, medical histories, and 3-generation pedigrees were collected from participants who provided samples for germline DNA analysis. RESULTS: Four hundred nineteen patients were deemed eligible, 302 were enrolled, and 298 were included in the final cohort. Clinically actionable variants were reported in 29 PDAC patients (9.7%), with 23 (7.7%) having a PGV associated with an increased risk for PDAC. Six of 23 individuals (26%) with PDAC-associated gene mutations did not meet currently established genetic testing criteria. According to guideline-based genetic testing, only 11 of the 23 PGVs (48%) in known PDAC genes would have been detected. Six additional patients (2%) had PGVs associated with an increased risk for other cancers. CONCLUSIONS: 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.
Subject(s)
Adenocarcinoma/genetics , Genetic Testing/methods , Germ Cells/metabolism , Germ-Line Mutation , Pancreatic Neoplasms/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Genetic Predisposition to Disease , Humans , Incidence , Male , Middle Aged , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathology , Prospective Studies , Young AdultABSTRACT
Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged 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.
Subject(s)
Leiomyoma/metabolism , Receptors, G-Protein-Coupled/metabolism , Repressor Proteins/metabolism , TOR Serine-Threonine Kinases/metabolism , Uterine Neoplasms/metabolism , Animals , Base Sequence , Disease Models, Animal , Female , Gene Expression , Gene Knockdown Techniques , Gene Regulatory Networks , Humans , Leiomyoma/genetics , Leiomyoma/pathology , Mice , Mice, Transgenic , RNA, Small Interfering/genetics , Receptors, G-Protein-Coupled/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/genetics , Signal Transduction , Tumor Cells, Cultured , Uterine Neoplasms/genetics , Uterine Neoplasms/pathologyABSTRACT
Endometriosis is a debilitating disease common in women of reproductive age characterized by pain and infertility. 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. To examine the role of MIF in the pathogenesis of endometriosis, we induced experimental disease in mice and examined the ability of the MIF antagonist, ISO-1, to reduce endometriotic implant size. 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. 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.
