Chemoprevention in Pediatric FAP

Collaborators

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Background

Chemoprevention remains an important strategy for the prevention of cancer particularly for individuals with hereditary cancer syndromes such as Familial Adenomatous Polypsis (FAP). This disorder is caused by an inherited somatic mutation in the APC gene that initiates the development of colon cancer through the same genetic pathway (mutant crypt cell to adenoma to cancer) as seen in sporadic colorectal cancer. However in FAP, there is near 100% penetrance for the development of CRC by the age of 50, almost two decades earlier than for the development of sporadic CRC in the general population.

Current Trial 

Recent trials suggest that combination therapy with an NSAID and Difluoromethylornithine (DFMO) may have potent synergistic effects on ademona development and regression in adults at risk for recurrent adenoma formation as well as FAP animal models. In an ongoing celecoxib/DFMO chemoprevention trial in FAP adults, a significant number of adult FAP patients were found to have measurable hearing deficits at enrollment, suggesting that hearing impairment may be associated with FAP. Prior human studies have suggested that DFMO use can be associated with temporary hearing loss however the significance of this observation remains to be determined. Currently there are no data in the medical literature that address the question: Does mutation of the APC gene convey hearing loss and at what age can it be detected?

Genetic analysis of the human ODC alleles has identified a single nucleotide polymorphism (ODC +316 G>A) that has been associated with altered survival in colorectal cancer and may play a role in DFMO responsiveness or function as a modifier gene in FAP. It is possible that patients that possess this polymorphism may have an altered response to DFMO influencing their susceptibility to DFMO associated Toxicity.

Laukaitis Lab Collaboration

The aim of this study is to obtain preliminary data on hearing status of children and adolescents between the ages of 6 and 19 with Familial Adenomatous Polypsis (FAP) and siblings of a similar age and socioeconomic matched controls. This study will focus on these patients with documented germline mutation in the APC gene, the causative genetic basis for FAP. DNA will be collected by mouth swab to asses for single nucleotide polymorphisms (SNPs) of the ODC gene, and SNP analysis will be done in our lab. The data from this preliminary study will be used in a future submission of a phase I chemoprevention grant in the same population.

Sample collection:

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