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Identification of common predisposing loci to hematopoietic cancers in four dog breeds.

ABSTRACT: Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans and dogs. The spontaneous canine model, which has clinical, epidemiological, and histological similarities with human HS and specific breed predispositions, provides a unique opportunity to unravel the genetic basis of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine-predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach as well as targeted next-generation sequencing, and imputation We combined several dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers, and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus, but also identified new loci on canine chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific loci suggested the existence of regulatory variants in non-coding regions and methylation mechanisms linked to risk haplotypes, which lead to strong cancer predisposition in specific dog breeds. We also showed that these canine cancer predisposing loci appeared to be due to the additive effect of several risk haplotypes involved in other hematopoietic cancers such as lymphoma or mast cell tumors as well. This illustrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study cancer initiation and progression.

SUBMITTER: Hedan B

PROVIDER: S-EPMC8016107 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143) of four Portuguese autochthonous breeds - Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data. RESULTS: Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds.A review of mtDNA haplotypes in dogs across the world revealed that: (a) breeds tend to display haplotypes belonging to different haplogroups; (b) haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c) haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d) genetic distances between breeds do not correlate with geography. CONCLUSION: MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal) and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog) and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the Azores Cattle Dog descended maternally from Northern European dogs rather than Portuguese mainland dogs. A review of published mtDNA haplotypes identified thirteen non-Portuguese breeds with sufficient data for comparison. Comparisons between these thirteen breeds, and the four Portuguese breeds, demonstrated widespread haplotype sharing, with the greatest diversity among Asian dogs, in accordance with the central role of Asia in canine domestication.

Project description:BackgroundApproximately 61 million Americans have a disability. Little research has explored whether disability is associated with subsequent diagnosis of cancer, the second-leading cause of death in the United States. The objective of this study was to explore associations between cancer and disability, focusing on 4 cancers that may present with nonspecific symptoms that could be conflated with aspects of disability, thus delaying cancer diagnoses. An analysis of a nationally representative survey using sampling weights to produce national estimates was performed.MethodsCivilian, noninstitutionalized US residents responding to the 2010-2017 National Health Interview Surveys totaling 259,392 Sample Adult Core survey respondents were included. We used self-reported functional status limitations to identify persons with movement difficulties (MD), complex activity limitations (CAL), and no disability. Multivariable regressions predicting cancer diagnosis included sociodemographic characteristics, tobacco use, body mass index, access to care indicators, and disability status.ResultsPersons with preexisting disability had significantly higher rates of cancer (ranging from 0.40 [SE, 0.05] for ovarian to 3.38 [0.14] for prostate) than did those without disability (0.20 [0.02] and 1.26 [0.04] for the same cancers; all P<.0001). Multivariable analyses found strong associations of preexisting MD and CAL with colorectal cancer, with adjusted odds ratios (aORs) of 1.5 (95% CI, 1.2-1.9) and 1.9 (1.5-2.4), respectively. For non-Hodgkin's lymphoma, the aOR for CAL was 1.5 (1.1-2.1). For prostate cancer, aORs for MD were 1.2 (1.0-1.3) and 1.1 (1.0-1.3) for CAL. Using cross-sectional survey data, we could only identify statistical associations, not causality.ConclusionsOur population-based analyses suggest that persons with disability may constitute a high-risk population, with higher cancer incidence. Optimizing appropriate screening and fully investigating new signs and symptoms are therefore critical for patients with disability.

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Identification of common predisposing loci to hematopoietic cancers in four dog breeds.

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