A novel mutation in the T8 microsatellite of 3-UTR CDK2-AP1 gene in MSI CRC

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DESCRIPTION (provided by applicant): . The objective of this application is to define the frequency and role of a recently discovered del T alternation in poly(T)8 in the 3'-UTR of the Cyclin Dependent Kinase-2- Associated Protein-1 (CDK2-AP1) gene in Microsatellite unstable (MSI) colorectal cancer (CRC). Current literature recognizes two pathways lead to invasive CRC. Microsatellite stable (MSS) pathway is the most common pathway, seen in approximately 80% of CRC cases, in which no microsatellite sequence alterations were observed. The other pathway is MSI pathway, explained in the remaining 20% of CRC cases, characterized by frame shift mutations and base-pair substitutions of the microsatellite DNA. CDK2-AP1 is a known growth suppressor in the etiology of RC. We previously reported that the CDK2-AP1 expression has been significantly decreased in human MS RC cell lines (Yuan et al., 2003) and its induction resulted in decreased cell proliferation and increased apoptosis (Kent et al., 2004). Recently, we detected a frequent, novel single alteration, del T in poly (T)8 of the 3'-UTR of the CDK2-AP1 gene in 25% of MSI CRC cell lines (3 of 12), is associated with decreased DK2-AP1 expression (Yuan et al., 2005). In a concurrent study by Ruggiero, described a similar poly T(8) alteration in 3'-UTR region of the CEACAM1 gene in human MSI CRC, strengthens our project. Based on our previously published findings, we hypothesize: 1). del T in a poly (T)8 of the 3'-UTR of the CDK2-AP1 gene is a frequent alteration in MSI CRC, 2) observed del T is a somatic alteration, associated with decreased expression of CDK2-AP1. In this proposed project, we will test our hypothesis by completion of he following Specific Aims: Specific Aim 1: a) We will determine the frequency of the del T in a poly (T)8 of he 3'-UTR of the CDK2-AP1 gene in human MSI CRC; b) To further determine this alteration is a somatic or a germline mutation, we will compare the identified positive CRC sample with normal tissue pairs. Specific Aim 2: We will characterize the role of this del T alteration in decreased expression of CDK2-AP1 in human MSI CRC. Completion of our proposed Specific Aims will advance our knowledge about the mechanism of decreased CDK2-AP1 expression in MMR deficient CRC. At the completion of this proposed pilot study, will urther determine del T alteration in a large number of CRC patients to identify high risk population.