Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common

Autor: Carlos E. Alvarez, Isain Zapata, Sara Zaldívar-López, Luis E. Moraes, Jennie L. Rowell, Elise Fiala, C. Guillermo Couto
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0106 biological sciences
Multifactorial Inheritance
Intersection union test
LASSO
Breeding
01 natural sciences
Genome
Canine
FGF9
Logistic regression modeling
Cohort Studies
CDKN2A
CDKN2B
Stepwise
Dog Diseases
BMPER
Genetics
0303 health sciences
Osteosarcoma
IGF1
Genomics
Breed
EWSR1
SVIL
symbols
Biotechnology
Research Article
lcsh:QH426-470
lcsh:Biotechnology
Bone Neoplasms
Biology
MARCO
MIR100HG
Canine Osteosarcoma
Risk Assessment
MTMR7
03 medical and health sciences
symbols.namesake
Dogs
TANGO2
lcsh:TP248.13-248.65
MTMR9
Animals
Genetic Predisposition to Disease
Survival rate
Gene
030304 developmental biology
Models
Statistical
NELL1
AQP4
lcsh:Genetics
Disease Models
Animal
Case-Control Studies
Mendelian inheritance
Retrogene
FBRSL1
BRINP3
010606 plant biology & botany
OTX2
Genome-Wide Association Study
Zdroj: BMC Genomics
BMC Genomics, Vol 20, Iss 1, Pp 1-14 (2019)
ISSN: 1471-2164
Popis: 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.
Databáze: OpenAIRE
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