The overall goal of this proposal is not only to confirm that cyclin D1 (CD1) G/A870 polymorphism results in a higher risk of progression from Barrett's esophagus (BE) with metaplasia to high-grade dysplasia (HGD) but also to [1] establish that this polymorphism results in functional consequences in the target tissues in the form of deregulated expression of CD1b, variant oncogenic protein, and [2] establish that combined assessment of CD1 genotype-phenotype further provides a stratified risk of progression to HGD. The long-term goal of our research is to discover and validate biomarkers of progression of metaplasia to HGD and identify high-risk populations for targeted surveillance. The incidence of esophageal adenocarcinoma (EAC) has dramatically risen in the West. BE is a pre-cancerous condition that carries up to 125-fold greater risk of progressing to EAC than the general population. Relatively few patients with BE develop EAC during their life-time, thus surveillance strategies for BE patients are challenging, because of difficulty to determine which patients are likely to progress to HGD and the high cost-benefit ratio of large scale annual endoscopic surveillance programs. Only a few biomarkers, representing genomic instability leading to the emergence of clonal diversity, have been validated to assess for risk of progression from high-grade dysplasia to cancer. However, we have no discriminating molecular or genetic biomarkers to identify individuals with BE metaplasia that are likely to progress to HGD. Clearly, such tools would be of critical importance. Our recent work in BE indicates that the CD1 single nucleotide polymorphism G/A870 promotes abnormal nuclear CD1 levels and enhances the acquisition of genomic instability, thereby leading to a more rapid development of EAC. The cyclin D1 G/A870 polymorphism is biologically functional since it has been associated with increased production of a variant cyclin D1 protein with oncogenic nuclear properties. We propose to: 1) Determine the association between CD1 G/A870 SNP and the risk of BE progression to High Grade Dysplasia (HGD);2) Measure the expression of nuclear CD1a and CD1b proteins in the target tissues and establish the association between CD1 protein levels and risk of progression to HGD;3) Establish that the combined assessment of CD1 genotype-phenotype produces a stratified risk of progression to HGD by using chromosome instability as surrogate biomarker. This genotype-phenotype pilot study will provide unique biological plausibility of the association of CD1 870 SNP with risk of progression to BE progression. Our studies will provide preliminary evidence of CD1b as a novel biomarker useful to identify high-risk populations that may be further selectively surveyed, using multiparameter risk assessment models, and targeted for tailor-made interventional preventive strategies.
The overall goal of the project is to retrospectively validate genotypic-phenotypic biomarkers of patient's susceptibility and target tissue vulnerability associated with progression of Barrett's esophagus metaplasia to high-grade dysplasia.
