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Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common
BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425649/ https://www.ncbi.nlm.nih.gov/pubmed/30890123 http://dx.doi.org/10.1186/s12864-019-5531-6 |
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author | Zapata, Isain Moraes, Luis E. Fiala, Elise M. Zaldivar-Lopez, Sara Couto, C. Guillermo Rowell, Jennie L. Alvarez, Carlos E. |
author_facet | Zapata, Isain Moraes, Luis E. Fiala, Elise M. Zaldivar-Lopez, Sara Couto, C. Guillermo Rowell, Jennie L. Alvarez, Carlos E. |
author_sort | Zapata, Isain |
collection | PubMed |
description | BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications. RESULTS: First, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG. CONCLUSIONS: Polygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-019-5531-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6425649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64256492019-04-01 Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common Zapata, Isain Moraes, Luis E. Fiala, Elise M. Zaldivar-Lopez, Sara Couto, C. Guillermo Rowell, Jennie L. Alvarez, Carlos E. BMC Genomics Research Article BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications. RESULTS: First, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG. CONCLUSIONS: Polygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-019-5531-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-19 /pmc/articles/PMC6425649/ /pubmed/30890123 http://dx.doi.org/10.1186/s12864-019-5531-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Zapata, Isain Moraes, Luis E. Fiala, Elise M. Zaldivar-Lopez, Sara Couto, C. Guillermo Rowell, Jennie L. Alvarez, Carlos E. Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title | Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title_full | Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title_fullStr | Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title_full_unstemmed | Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title_short | Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common |
title_sort | risk-modeling of dog osteosarcoma genome scans shows individuals with mendelian-level polygenic risk are common |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425649/ https://www.ncbi.nlm.nih.gov/pubmed/30890123 http://dx.doi.org/10.1186/s12864-019-5531-6 |
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