Abstract 4598: Allelic loss of NDST4, a putative tumor suppressor gene, is associated with tumor progression of colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is one of the most common malignancies in the world. Many molecular abnormalities have been reported in CRC, of which accumulated alterations of tumor suppressor genes (TSGs) and proto-oncogenes are required for the disease development. Genomic deletion is reflected in a genetic mechanism called loss of heterozygosity (LOH). Allelic deletion at tumor suppressor loci is common in all human cancers, and contributes to TSG silencing. By allelotyping with 22 polymorphic microsatellite markers spanning from chromosome 4pter to 4qter, we first defined the most frequent LOH region at 4q27, which occurred allelic imbalance in 32.1% (34/106) of colorectal carcinomas. After fine deletion mapping in these carcinomas, we further identified a minimal region harboring one gene with known functions, named NDST4. By quantitative RT-PCR, NDST4 expression could hardly be detected in 10 of 11 CRC cell lines, and was downregulated in 57.7% (30/52) of CRC tumors. Importantly, NDST4 expression was significantly decreased in tumors compared with matched normal mucosa or adenomas (P<0.01). In addition, immunohistochemistry staining of CRC tissue array also demonstrated decreased protein levels in Dukes’ stages C and D tumors. We further directly determined the genetic loss of NDST4 in colorectal tumors by use of 3 microsatellite markers located upstream of and inside NDST4 gene. Sixty (29.9%) of 201 carcinomas exhibited LOH at one or more microsatellite loci. Allelic loss of NDST4 was increased in patients with late stage of tumor extension (T3 and T4), lymph node involvement and distant metastasis (P=0.011, 0.053 and 0.058, respectively). Notably, LOH at MS5979 locus, a newly identified microsatellite marker within NDST4 gene, was significantly associated with disease progression of Dukes’ stages (P<0.01). Taken together, NDST4 could be a CRC-associated TSG and its genetic loss might be involved in tumor progression. In addition, the LOH assay established in the study could be a potential diagnostic and prognostic test in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4598. doi:1538-7445.AM2012-4598