COSMIC: a curated database of somatic variants and clinical data for cancer.

The Catalogue Of Somatic Mutations In Cancer (COSMIC), https://cancer.sanger.ac.uk/cosmic, is an expert-curated knowledgebase providing data on somatic variants in cancer, supported by a comprehensive suite of tools for interpreting genomic data, discerning the impact of somatic alterations on disease, and facilitating translational research. The catalogue is accessed and used by thousands of cancer researchers and clinicians daily, allowing them to quickly access information from an immense pool of data curated from over 29 thousand scientific publications and large studies. Within the last 4 years, COSMIC has substantially expanded its utility by adding new resources: the Mutational Signatures catalogue, the Cancer Mutation Census, and Actionability. To improve data accessibility and interoperability, somatic variants have received stable genomic identifiers that are associated with their genomic coordinates in GRCh37 and GRCh38, and new export files with reduced data redundancy have been made available for download.

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus.

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1-13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10-4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

Review on Canine Oral Melanoma: An Undervalued Authentic Genetic Model of Human Oral Melanoma?

Oral melanoma (OM) is a highly aggressive tumor of the oral cavity in humans and dogs. Here we review the phenotypic similarities between the disease in these 2 species as the basis for the view that canine OM is a good model for the corresponding human disease. Utility of the "canine model" has likely been hindered by a paucity of information about the extent of the molecular genetic similarities between human and canine OMs. Current knowledge of the somatic alterations that underpin human tumorigenesis and metastatic progression is relatively limited, primarily due to the rarity of the disease in humans and consequent lack of opportunity for large-scale molecular analysis. The molecular genetic comparisons between human and canine OMs that have been completed indicate some overlap between the somatic mutation profiles of canine OMs and a subset of human OMs. However, further comparative studies featuring, in particular, larger numbers of human OMs are required to provide substantive evidence that canine OMs share mechanisms of tumorigenesis with at least a subset of human OMs. Future molecular genetic investigations of both human and canine OMs should investigate how primary tumors develop a metastatic gene expression signature and the genetic and epigenetic alterations specific to metastatic sites. Such studies may identify genetic alterations and pathways specific to the metastatic disease which could be targetable by new drugs.

A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers.

Mast cell tumours are the most common type of skin cancer in dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. In this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as cancer.

Identification of molecular genetic contributants to canine cutaneous mast cell tumour metastasis by global gene expression analysis.

Cutaneous mast cell tumours are one of the most common canine cancers. Approximately 25% of the tumours metastasise. Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations. Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy. Available prognostic tests do not reliably predict whether a tumour will metastasise. In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise. The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis. Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery. Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility. Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis. Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing. Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90-100% and 70-100%, respectively. The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR.

Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours.

Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.

Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours.

Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.

BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.

Of dogs and men: comparative biology as a tool for the discovery of novel biomarkers and drug development targets in osteosarcoma.

The similarities between human and canine osteosarcoma with regard to histology, biological behavior and molecular genetic alterations suggest that the dog provides a supplementary model for the development and preclinical testing of novel therapeutics. Counter intuitively, careful examination of the differences between OS in the two species may also be rewarding in terms of increasing our understanding of the pathogenesis of this cancer. This review will discuss the arguments in favor of the "dog model" and outline how the evaluation of treatment strategies in dogs has indicated avenues for improvement of protocols for human patients.

Gene expression profiles of metabolic enzyme transcripts in Alzheimer's disease.

The successfully functioning brain is a heavy user of metabolic energy. Alzheimer's disease, in which cognitive faculties decline, may be due, at least in part, to metabolic insufficiency. Using microarray analysis and quantitative RT-PCR, the expression of mRNA transcripts involved in glucose metabolism was investigated in Alzheimer's diseased post-mortem human hippocampal samples. Of the 51 members of the glycolytic, tricarboxylic acid cycle, oxidative phosphorylation, and associated pathways investigated by qPCR, 15 were confirmed to be statistically significantly (p<0.05) down-regulated in Alzheimer's disease. This finding suggests that reductions in the levels of transcripts encoded by genes that participate in energy metabolism may be involved in Alzheimer's disease.

Dogs really are man's best friend--canine genomics has applications in veterinary and human medicine!

In 2003, the US National Human Genome Research Institute (NHGRI) agreed to fund a project to sequence the entire genome of a boxer dog named Tasha. Although the USA is a country of dog lovers, with approximately 38 million households owning one or more dogs, why did one of the National Institutes of Health countenance the use of 30 m dollars for such a purpose? The answer is that the NHGRI recognised the value of the dog as an unrivalled model for the study of human disease. In this paper, the reasons why the dog is such a good model are examined. Examples of where the study of disease in dogs is increasing the understanding of the genetic basis of human disease, of the development of improved diagnostic assays and of the evaluation of clinical therapies are provided.