Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube.

Unlabelled: Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC.

The kinase activity of PKR represses inflammasome activity.

The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR.

Notch1 Activation or Loss Promotes HPV-Induced Oral Tumorigenesis.

Viral oncogene expression is insufficient for neoplastic transformation of human cells, so human papillomavirus (HPV)-associated cancers will also rely upon mutations in cellular oncogenes and tumor suppressors. However, it has been difficult so far to distinguish incidental mutations without phenotypic impact from causal mutations that drive the development of HPV-associated cancers. In this study, we addressed this issue by conducting a functional screen for genes that facilitate the formation of HPV E6/E7-induced squamous cell cancers in mice using a transposon-mediated insertional mutagenesis protocol.

Homology-mediated end-capping as a primary step of sister chromatid fusion in the breakage-fusion-bridge cycles.

Breakage-fusion-bridge (BFB) cycle is a series of chromosome breaks and duplications that could lead to the increased copy number of a genomic segment (gene amplification). A critical step of BFB cycles leading to gene amplification is a palindromic fusion of sister chromatids following the rupture of a dicentric chromosome during mitosis. It is currently unknown how sister chromatid fusion is produced from a mitotic break.

Identification of disease-associated DNA methylation in B cells from Crohn's disease and ulcerative colitis patients.

Background: Changes in the methylation status of inflammatory bowel disease (IBD)-associated genes could significantly alter levels of gene expression, thereby contributing to disease onset and progression. We previously identified seven disease-associated DNA methylation loci from intestinal tissues of IBD patients using the Illumina GoldenGate BeadArray assay.

Aims: In this study, we extended this approach to identify IBD-associated changes in DNA methylation in B cells from 18 IBD patients [9 Crohn's disease (CD) and 9 ulcerative colitis (UC)].

CCL2 expression in primary ovarian carcinoma is correlated with chemotherapy response and survival outcomes.

CCL2, a chemokine, is expressed in normal human ovarian epithelium but down-regulated in ovarian adenocarcinomas. The association of CCL2 expression with chemotherapy response, invasion and survival outcomes was studied in patients with primary ovarian cancer (OC) and in ovarian cancer cell lines (OCCLs). Tumor specimens (>80% tumor) from patients with primary, advanced serous OC obtained at the time of cytoreductive surgery was used to isolate total RNA.

Genes regulated by Nkx2-3 in siRNA-mediated knockdown B cells: implication of endothelin-1 in inflammatory bowel disease.

Nkx2-3 gene variants are strongly associated with inflammatory bowel disease (IBD) and its expression is up-regulated in Crohn's disease (CD). However, the nature of its role underlying IBD pathogenesis is unknown. We investigated the genes regulated by Nkx2-3 using cDNA microarray.

Differential expression in clear cell renal cell carcinoma identified by gene expression profiling.

Purpose: Gene expression profiling has been shown to provide prognostic information on patients with solitary sporadic renal cell carcinoma. To our knowledge there is no reliable way to differentiate synchronous renal metastasis from bilateral primary tumors in patients with bilateral renal cell carcinoma. We present data using a custom kidney cancer cDNA array that can predict the outcome in patients with unilateral and bilateral renal cell carcinoma.

GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome.

Background: GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.

Methods/principal Findings: In this study, we created and characterized the phenotype of GPRC6A(-/-) mice.

A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L.

Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases. 2'-5' oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNase L. Although RNase L is required for a complete IFN antiviral response and mutations in the RNase L gene (RNASEL or HPC1) increase prostate cancer rates, it is unknown how 2-5A affects these biological endpoints through its receptor, RNase L.

Identification of a novel extracellular cation-sensing G-protein-coupled receptor.

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family.

Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport.

Huntington's and Kennedy's disease are autosomal dominant neurodegenerative diseases caused by pathogenic expansion of polyglutamine tracts. Expansion of glutamine repeats must in some way confer a gain of pathological function that disrupts an essential cellular process and leads to loss of affected neurons. Association of huntingtin with vesicular structures raised the possibility that axonal transport might be altered.