Kits and methods for assessing patient’s susceptibility to cancer or adenoma recurrence, and process for identifying inhibitors of carcinogenesis.

Lankenau Institute for Medical Research
posted on 02/21/2008

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The gene ODC encodes for Ornithine decarboxylase, a rate-limiting enzyme in the biosynthesis of polyamines, ubiquitous cellular components that are essential for protein synthesis, mRNA translation, and DNA replication. In studying ODC genes, Dr. O’Brien and colleagues discovered single nucleotide polymorphisms (SNPs) for a regulatory region in the ODC gene that distinguishes the A- from G- allele and correlates with increased susceptibility to various cancers. Based on these SNPs, Dr. O’Brien and colleagues have invented kits and developed methods for assessing the susceptibility of individuals for carcinogenesis.

The importance of ODC polymorphism in modulating cancer susceptibility was further demonstrated by recent analyses of two independent adenoma recurrence trials that report a significant influence of genetic variation at the ODC locus and risk of adenoma recurrence, especially in aspirin users (references 1 and 2). Analysis showed that people with the AA- genotype and who take aspirin regularly have a 60-90% risk reduction for adenoma recurrence compared to people with a GG- genotype who do not take aspirin regularly. This is one of the largest risk reductions for adenoma recurrence reported for any intervention.

These impressive results confirm that the present innovation has clinical utility, since it would identify individuals with the AA- genotype, at higher risk of carcinogenesis or adenoma recurrence, as candidates for prophylactic aspirin treatment.

References:
1. O’Brien, T., Guo, Y., Rosson, D., Boorman, D., and Harris, R.B. 2000. Functional analysis of human ornithine decarboxylase alleles. Cancer Res 60:6314-6317.

2. Martinez, M.E., O’Brien, T.G., Futz, K.E., et al. 2003. Pronounced reduction in adenoma recurrence associated with aspirin use and polymorphism in theornithine decarboxylase gene. Proc Natl Acad Sci, 100, 7859-7864.

The present innovation includes kits and methods for assessing the susceptibility for carcinogenesis or adenoma recurrence. It is based on the discovery that the presence of the A- allele of the ODC gene in an individual, and particularly the presence of two copies of the A- allele, is predictive of a high incidence of carcinogenesis. The presence of the A- allele is, for example, highly predictive of an individual’s susceptibility to development of environmentally-induced squamous cell carcinoma.

Based on clinical studies, identification of individuals at higher risk of adenoma recurrence or of developing cancer (i.e. AA- allele) could be treated with drugs, possibly aspirin, for added protection.

The kits and methods issued from this innovation are applicable for substantially any epithelial cancer, including, for example, skin cancers such as squamous cell carcinoma, cancers of the digestive system, esophageal cancers, gastric cancers, colon cancers, prostate cancers, breast cancers, hematopoietic cancers, lung cancers, melanomas, and cervical cancers.


An added benefit of the present innovation includes a method of assessing whether a test compound is an inhibitor of carcinogenesis. To that end, ornithine decarboxylase activity is assessed in a cell comprising the A- allele of the human ODC gene in the presence of an inducer of carcinogenesis and in the presence or absence of the test compound. If ornithine decarboxylase activity is lower in the presence of the test compound than in the absence of the test compound, then the test compound is an inhibitor of carcinogenesis

This innovation can be easily applied to assess cancer susceptibility in mammals. This innovation can be combined to substantially any method of detecting an allele of the ODC gene, including for example, hybridization, amplification, or sequencing methods. This innovation allows for simple and extremely reliable assessments of carcinogenesis or for identifying inhibitors of carcinogenesis.

The cost associated with the use of this innovation is minimal. Likewise, the treatment of patients at higher risk of carcinogenesis would require very limited expenses if drugs such as aspirin are used.