The ESR1 gene is associated with risk for canine mammary tumours

Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P-Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P-Bonf = 8.8E-32, best P-BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research

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 (p(raw) = 5.6x10(-7), p(perm) = 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 (p(raw) = 1.97x10(-5) and p(raw) = 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

Large outbreak of mumps virus genotype G among vaccinated students in Norway, 2015 to 2016

From 6 September 2015–May 2016, a large mumps outbreak occurred among vaccinated students in Norway. A case was defined as a person presenting with a clinical mumps infection, notified between 1 September 2015 and 30 June 2016. Confirmed cases had positive laboratory confirmation and probable cases had an epidemiological link; PCR-positive specimens were genotyped. A total of 232 cases were notified (230 confirmed) with median age of 23 years (range 4–81) and 61% were male. Of 68 (30%) confirmed cases that were genotyped, 66 were genotype G and associated with the outbreak. Cases that had received two doses of the measles-mumps-rubella (MMR) vaccine had reduced risk of hospitalisation (adjusted relative risk (aRR): 0.14; 95%CI: 0.03–0.57), mumps-related orchitis (aRR: 0.21; 95% CI: 0.08–0.55) and severe outcome (aRR: 0.25; 95% CI: 0.10–0.62) compared with those unvaccinated. A third dose of the vaccine was offered to approximately 1,300 fully vaccinated close contacts and subsequently reported cases decreased. This large outbreak, occurring among predominately vaccinated students, suggests the current genotype A vaccine offers suboptimal protection against mumps genotype G. We recommend maintaining high vaccination coverage and offering the vaccine to all unvaccinated individuals

Association results for chromosome 27.

<p><b>(A)</b> Chromosome 27 with association results colour-coded according to pair-wise LD (r²) with the top two SNPs (index 1 = chr27:745,156 bp and 2 = chr27:7,706,463 bp). <b>(B)</b> Minor allele frequency plot over chromosome 27. <b>(C)</b> Association results for the merged and imputed GWAS and sequence candidate SNPs dataset at the 0.7 Mb peak. The top SNP (chr27:735,281 bp) is located 418 bp upstream of <i>LACRT</i>, SNP position indicated by red arrow. Gene annotations are lifted over from the human genome. <b>(D)</b> Association results for the 7.7 Mb region. The top SNP (chr27:7,706,463 bp) is potentially located in an intron of <i>SLC38A4</i>.</p

Top ten GWAS regions defined by linkage disequilibrium (cut-off p<0.1 and r²>0.2).

<p>Top ten GWAS regions defined by linkage disequilibrium (cut-off p<0.1 and r²>0.2).</p

Haplotypes in the chromosome 11 candidate region.

<p><b>(A)</b> Phylogenetic tree displaying haplotype relationship of 15 SNPs in the candidate region on chromosome 11. The 51 haplotypes can be formed into three groups based on the tree clusters (separated by dashed lines). <b>(B)</b> Case/control frequencies in the three haplotype groups in the ESS cohort. There is a lower proportion of cases in haplotype group 1 compared to group 3.</p

Genome-wide association results.

<p><b>(A)</b> Quantile-quantile plot displaying a lambda of 1.00, indicating no residual inflation. Thin lines indicate 95% CI. SNPs with -log₁₀(p) values > 4 deviates from the expected distribution and are associated with CMT. <b>(B)</b> Manhattan plot displaying the results from the GWAS based on the Swedish ESS Illumina 170K genotypes. Genome-wide significance is reached for one SNP on chromosome 11 (73,290,522 bp) and nominal association is reached for seven SNPs on chromosomes 11 and 27.</p

SNPs associated with CMT.

<p>SNPs associated with CMT.</p