The most common primary malignant tumor of the bone is Osteosarcoma (OSA). The prognosis for patients with metastatic OSA is poor, with a 5 year event free survival rate of only 20%. Yet, little is known about the genetic predisposition of OSA in any organism. Copy number variation (CNV), a type of genetic variation has been implicated in the development of human OSA. However, further progress is complicated by the high genetic heterogeneity of human populations. Dog OSA is genetically and phenotypically similar to human, and dog breeds have tremendously reduced heterogeneity. Thus, dogs have vast potential to establish genetic factors that influence naturally occurring OSA. Fine genetic mapping can be done using related breeds that are likely to share the same founder mutation. The highest incidence of canine OSA is in the American Greyhound (odds ratio of 17), but strikingly the closely related Spanish Greyhound (or Galgo) does not have increased risk. This proposal takes advantage of the very high and low incidence of OSA in closely related breeds in order to identify OSA-associated variation.
Aim 1 is to discover common CNV in closely related dog breeds with very high and low OSA risk.
Aim 2 is to test CNVs present in American, but not Spanish, Greyhounds in a case-control association study of OSA. Ultrahigh-resolution array comparative genomic hybridization of DNA samples from American and Spanish Greyhounds will be used to discover the common CNVs. 100 CNVs will be validated by breakpoint-specific PCR where possible, as well as Southern blotting and Q-PCR. Genotyping will be done to detect CNV presence/absence using CNV allele specific PCR assays. Discovery of a naturally occurring CNV causing or modifying the course of OSA in dogs would represent the first genetic model of OSA. This would allow for further research in the treatment and prevention of OSA and other cancers in humans. Two research foci of NINR are health promotion and disease prevention. A study utilizing a canine model for CNV would be the basis for developing further research studies to explore the role of CNV in human health and disease. The findings will not only address national nursing research priorities but may also have strong clinical implications for other patient populations. Little is known about the molecular processes of osteosarcoma, or how it can be prevented and treated. Human genetic diversity is so great that it is difficult to know what variation could be associated with osteosarcoma. In this project, we will identify disease variation in closely related dog breeds with extremely high osteosarcoma risk and without elevated risk. Because this dog cancer is very similar to that of humans, this information will lead to new therapeutic approaches in humans.
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