Abstract 5145: Integrative analysis of multidimensional colorectal cancer molecular profiles reveals an aggressive subpopulation characterized by specific gene methylation/expression patterns.
Authors: Isella Claudio 
Published: August 2014

Colorectal cancer (CRC) is clinically and molecularly heterogenous. With the advent of approaches based on multidimensional genomic profiling, such as the one carried out by The Cancer Genome Atlas (TCGA) consortium, new analytical tools have to be developed and employed to fully integrate and analyze multiple layers of molecular and clinical annotation, and so highlight previously unknown features of the disease.

To tackle this issue, we reasoned that highly efficient and integrative visualization of molecular and clinical data may enable intuitive identification of recurrent correlation patterns within complex datasets. We therefore developed a 3D-graphical, real-time interactive software, the “GenomeCruzer," that greatly accelerates global data visualization and analysis, facilitating the rapid screening of a high number of working hypotheses and allowing swift prioritization of the most promising ones.

We initially focused on a publicly available dataset of expression and methylation profiles provided by the TCGA consortium on a panel of 145 colon cancer specimens, and selected a subset of 3600 genes expressed with high variability across the dataset. Unsupervised clustering of genes based on their methylation profiles across samples identified three main subsets, displaying, respectively, high, low and intermediate overall methylation status. Data visualization and analysis with GenomeCruzer revealed that the three gene methylation clusters were clearly associated with three patient subgroups: patients with a CpG island methylator phenotype (CIMP) were mostly captured, as expected, by the high methylation gene subgroup, while the 1471-gene cluster with an alternative methylation pattern defined a subgroup of 75 patients, that we named “alternative methylator phenotype” (AMP), most notably enriched for Stage IV cases (o/e = 1.7, p.val &lt; 1.10-4) and depleted of MSI-H patients (o/e =0.21, 1*10-5). Integrative analysis of gene expression and methylation for the AMP patient group revealed transcriptional modules associated with interferon-alfa signalling (p &lt; 10-7, downregulated in AMPs) and with protein translation (p&lt; 10-6, upregulated in AMPs). Expression profiles obtained from the Cancer Cell Encyclopaedia were subsequently analysed to verify that expression of such modules occurs in cancer cells and is not derived from infiltrating cells.

These data show that integrative analysis of multidimensional clinical and molecular datasets such as those provided by the TCGA can be greatly facilitated by ad-hoc developed software like the GenomeCruzer, providing unprecedented insight into the biology of cancer and defining new cancer subtypes of potential clinical relevance.

Citation Format: Claudio Isella. Integrative analysis of multidimensional colorectal cancer molecular profiles reveals an aggressive subpopulation characterized by specific gene methylation/expression patterns. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5145. doi:10.1158/1538-7445.AM2013-5145