Abstract 1157: Increased expression of RecQ helicases in sporadic primary colorectal cancers
Authors: Victoria Valinluck Lao, Kelly T. Carter, Peter S. Rabinovitch, Piri Welcsh, William M. Grady
Journal: Cancer Research (2012)

Abstract The RecQ helicase family of enzymes regulate nucleic acid metabolism through the major activity of unwinding double stranded nucleic acids. Heritable loss of RECQ helicase expression results in human syndromes associated with an elevated risk of cancers including colorectal cancer (CRC). In vitro studies have shown that loss of function of WRN and/or BLM increases sensitivity to killing by DNA damaging chemotherapeutic agents. Thus, over-expression of these helicases may mediate tumor resistance to DNA damaging chemotherapeutic agents, whereas under-expression may identify a population of tumors that may be more susceptible. Currently, the literature with regards to the expression status of these enzymes in CRC is sparse. In this study, we assess the expression of all five members of the RECQ helicase family (WRN, BLM, RECQL, RECQL4 and RECQL5) in 32 sporadic primary colorectal cancer cases with matched normal colonic mucosa using quantitative real-time PCR. The results show a significant increase in the fold change of RECQ helicase expression in tumor as compared to the matched normal mucosa, using the Wilcoxon Signed Rank test with a theoretical median of 1. The results are as follows: WRN median=1.191, mean=1.347, SD=0.6189, p-value=0.0043; BLM median=4.146, mean=12.88, SD=24.86, p-value &amp;lt; 0.0001;RecQL median=1.638, mean=1.806, SD=1.145, p-value=0.0002;RecQL4 median=4.384, mean=4.745, SD=4.167, p-value &amp;lt;0.0001; RecQL5 median=1.087, mean=1.293, SD=0.7853, p-value=0.0487. Subgroup analyses of the expression of each RECQ helicase by stage using the Kruskal-Wallis test show no significant difference between stages I-IV of CRC. However, the data show that 12/32 cases had an increase in the expression of all RECQ helicases, whereas only one case had a decrease in all five RECQ helicases as compared to the matched normal colonic mucosa. Cluster analyses using both the Ward Algorithm and Complete Linkage with the Furthest Neighbor method revealed two distinct clusters that are similar in their pattern of RECQ Helicase expression. These distinct clusters may represent molecular subgroups of colorectal cancers [e.g. microsatellite unstable (MSI), microsatellite stable (MSS), or CpG Island Methylator Phenotype (CIMP)], which is the subject of future investigation. These data show an increase in RECQ helicase expression in CRC as compared to normal, suggesting that deregulation of RECQ helicase activity may play a role in the pathogenesis of colorectal cancer. Although the functional significance of the magnitude of expression has yet to be determined, the wide range in fold change values seen with BLM and RECQL4 suggest the expression of status of one or more of these RECQ helicases may prove as a predictive marker for responsiveness to therapy with DNA damaging agents, which could be used to personalize cancer therapy. 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 1157. doi:1538-7445.AM2012-1157