Abstract
Abstract Colorectal cancer (CRC) has been the second leading cause of cancer-related deaths due in part to a low compliance rate (<50%) of the current screening method, an invasive colonoscopy, resulting in failure of detecting cancer early in its curative stages. 20% of CRCs are only detected once the cancer has spread to a distant site, drastically reducing the 5-year survival rate from 90% to 12%. In order to improve the success of early detection methods of CRC, we have focused on developing non-invasive, multi-biomarker detection assays designed to identify CRC-associated genetic alterations. The genetic alterations of four genes, (mutations of the KRAS (muKras) and BRAF V600E (muBRAF) genes and aberrant hypermethylation of the Vimentin (mVIM) and Septin9 (mSEPT9) genes, have shown to be potential biomarkers of CRC through stool or serum-derived DNA. We set out to show that these four biomarkers could be used as a panel for a non-invasive urine test of CRC in a highly specific and sensitive manner. We have previously demonstrated that urine contains circulation-derived low molecular weight (LMW) DNA (<300 bp), which suggests that LMW urine DNA could be used to detect CRC-associated genetic alterations. A blinded concordance study was used to validate mVIM as a biomarker for CRC between 20 urine samples and the corresponding tissue sample. We have developed a locked nucleic acid (LNA) clamp and a Simple Probe to distinguish mVIM from normal VIM suitable for fragmented short DNA templates. By using this assay, we indicated that mVIM can be detected from LMW urine DNA, and it has the potential to serve as a CRC-specific biomarker (Song et al., 2012). This LNA-clamp short-qPCR assay has been adapted for quantitation of muBRAF, muKRAS, and mSEPT9, for testing these biomarkers with open-labeled CRC samples. In addition, a prevalidation study is in progress with blinded CRC samples to confirm the specificity and sensitivity of these genetic biomarkers. References Song, B. P., Jain, S., Lin, S. Y., Chen, Q., Block, T. M., Song, W., ... & Su, Y. H. (2012). Detection of hypermethylated vimentin in urine of patients with colorectal cancer. The Journal of Molecular Diagnostics, 14(2), 112-119. Citation Format: Adam W. Clemens, Selena Lin, Surbhi Jain, Sitong Chen, Ying-Hsiu Su, Wei Song. Detection of colorectal cancer-associated genetic alterations in urine of patients with CRC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2014-877
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