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

CCR2-V64I polymorphism is associated with increased risk of cervical cancer but not with HPV infection or pre-cancerous lesions in African women

<p>Abstract</p> <p>Background</p> <p>Cervical cancer, caused by specific oncogenic types of human papillomavirus (HPV), is the second most common cancer in women worldwide. A large number of young sexually active women get infected by HPV but only a small fraction of them have persistent infection and develop cervical cancer pointing to co- factors including host genetics that might play a role in outcome of the HPV infection. This study investigated the role of <it>CCR2-V64I </it>polymorphism in cervical cancer, pre-cancers and HPV infection in South African women resident in Western Cape. <it>CCR2-V64I </it>polymorphism has been previously reported to influence the progression to cervical cancer in some populations and has also been associated with decreased progression from HIV infection to AIDS.</p> <p>Methods</p> <p>Genotyping for <it>CCR2-V64I </it>was done by PCR-SSP in a case-control study of 446 women (106 black African and 340 mixed-ancestry) with histologically confirmed invasive cervical cancer and 1432 controls (322 black African and 1110 mixed-ancestry) group-matched (1:3) by age, ethnicity and domicile status. In the control women HPV was detected using the Digene Hybrid Capture II test and cervical disease was detected by cervical cytology.</p> <p>Results</p> <p>The <it>CCR2-64I </it>variant was significantly associated with cervical cancer when cases were compared to the control group (P = 0.001). Further analysis comparing selected groups within the controls showed that individuals with abnormal cytology and high grade squamous intraepitleial neoplasia (HSIL) did not have this association when compared to women with normal cytology. HPV infection also showed no association with <it>CCR2-64I </it>variant. Comparing SIL positive controls with the cases showed a significant association of <it>CCR2-64I </it>variant (P = 0.001) with cervical cancer.</p> <p>Conclusions</p> <p>This is the first study of the role of <it>CCR2-V64I </it>polymorphism in cervical cancer in an African population. Our results show that <it>CCR2-64I </it>variant is associated with the risk of cervical cancer but does not affect the susceptibility to HPV infection or HSIL in South African women of black and mixed-ancestry origin. This result implies that the role of CCR2 is important in invasive cancer of the cervix but not in HPV infection or in the development of pre-cancers.</p

Identification of two novel mammographic density loci at 6Q25.1

INTRODUCTION: Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci. METHODS: Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account. RESULTS: Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10(−8) for percent MD and P = 8.7 × 10(−9) for absolute MD) and AREG (rs10034692, P = 6.7 × 10(−9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10(−9) for percent MD and P = 2.5 × 10(−8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10(−8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response. CONCLUSIONS: We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0591-2) contains supplementary material, which is available to authorized users

Sea-bed scattering and reflection contributions to the short-range acoustic impulse response: measurements and modelling

A short-range experiment in shallow water has been performed to assess the various contributions to the impulse response. A sound source emitted pulses, centered at 25 kHz, that were registered by an array some 50 m away. The impulse response recordings show initial isolated peaks, followed by long decaying spiky tails. A 3-D ray model, Rev3D, was used to model the measured time traces. The initial peaks were identified as direct and multi-path propagation arrivals, while the decaying tails arise from bistatic reverberation involving the bottom and the sea surface in an elliptical area, with the source and receiver positions as focal points. Beam-forming with the receiver array was applied to locate the parts of the bottom with the most significant contributions to the impulse response, and to suggest an improved reflection-coefficient as well as scattering-kernel values. Rev3D modelling with energy-density maps for selected time intervals, and time traces for energy-weighted averages of various parameters, such as the arrival angles at the array, was also applied for this purpose

Numerical investigation of out-of-plane sound propagation in a shallow water experiment

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