Abstract #LB-276: Intersection of genomic and epigenomic gene approaches identifies global disruption of the ECM pathway in colorectal cancer (2009)

Growing evidence shows that epigenetic abnormalities participate with genetic alterations in human cancers. Recent genome-wide sequencing efforts of multiple cancers has identified a large number of mutations, albeit most occurring with low frequencies. Significant numbers of mutations in other pathways (such as PIK3KC ) have been identified but little is known about the consequences of these events. Recent literature has also shown that pathways rather than individual genes may control the course of tumorigenesis. In this study, by intersecting the genomic and epigenomic landscapes of breast and colorectal cancers (CRC) we provide key insights into one such pathway. Using an unbiased genome-wide approach, we identified 29 genes which are inactivated by both genetic and epigenetic mechanisms in breast and CRC. CRC have an increased frequency of epigenetic alterations of these genes than breast cancers. We next queried an extensive gene ontology set (MetaCore) and discovered that the extracellular matrix (ECM) maintenance and remodelling pathway is globally disrupted by genetic and epigenetic alteration in nearly every CRC. Interestingly, nearly half of the genes that we identified to be both mutated and hypermethylated in breast and CRC (13/29 genes) mapped to the ECM pathway, suggesting the global disruption of this pathway in CRC. Alterations in the ECM pathway are thought to be important in tumorigenesis and the, so called, epithelial-mesenchymal transition (EMT). Recent data has shown that tumors with EMT have an embryonic stem (ES) cell like gene expression pattern indicating a very primitive phenotype for the cells which have acquired this. Given this, we compared expression of the 13 genes in the ECM pathway in ES cell lines and found that 12 out of the 13 ECM genes are also silenced in hES cells. Another correlate of the juxtaposition of embryonic gene expression patterns and EMT is that the tumors involved are aggressive cancers. To further explore this question, we queried a large cohort of CRC (n=147; Stages 1-4) for correlation between survival and methylation of some of the key genes ( IGFBP3 , EVL , NTNG1 and CD109 ) in the ECM pathway. Strikingly, we observed almost 3-fold increased risk for mortality among patients with methylated IGFBP3 and EVL as compared to patients with unmethylated IGFBP3 and EVL respectively, after adjusting for age and stage ( IGFBP3 HR=2.58, 95%CI:1.37-4.87, p=0.004; EVL HR=2.48, 95%CI:1.07-5.47, p=0.034). Patients with concurrent methylation of multiple genes in the ECM pathway have an incrementally increased risk of mortality in multivariate analysis (Ex: EVL and IGFBP3 methylation HR=4.18, 95% CI: 1.5-11.6). In summary, silencing of the ECM pathway is ubiquitous in CRC and may affect prognosis. Furthermore, our data illustrates the role of integrative genome-wide strategies in highlighting key pathways in cancer and novel treatment paradigms. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-276.