Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which, by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21, and 9q31.2. We identified interaction peaks between putative regulatory elements (''bait fragments'') within the captured regions and ''targets'' that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC; and target lncRNAs included DIRC3, PVT1, and CCDC26. For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlated with the published risk variant and that mapped within the bait end of an interaction peak. In vivo ChIP-qPCR data show that one of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant.

Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Candida Gene Order Browser (CGOB) was developed as a tool to visualize and analyze synteny relationships in multiple Candida species, and to provide an accurate, manually curated set of orthologous Candida genes for evolutionary analyses. Here, we describe major improvements to CGOB. The underlying structure of the database has been changed significantly. Genomic features are now based directly on genome annotations rather than on protein sequences, which allows non-protein features such as centromere locations in Candida albicans and tRNA genes in all species to be included. The data set has been expanded to 13 species, including genomes of pathogens (C. albicans, C. parapsilosis, C. tropicalis, and C. orthopsilosis), and those of xylose-degrading species with important biotechnological applications (C. tenuis, Scheffersomyces stipitis, and Spathaspora passalidarum). Updated annotations of C. parapsilosis, C. dubliniensis, and Debaryomyces hansenii have been incorporated. We discovered more than 1,500 previously unannotated genes among the 13 genomes, ranging in size from 29 to 3,850 amino acids. Poorly conserved and rapidly evolving genes were also identified. Re-analysis of the mating type loci of the xylose degraders suggests that C. tenuis is heterothallic, whereas both Spa. passalidarum and S. stipitis are homothallic. As well as hosting the browser, the CGOB website (http://cgob.ucd.ie) gives direct access to all the underlying genome annotations, sequences, and curated orthology data.