EARLY DIAGNOSIS AND EXPRESSION PROFILING CLASSIFICATION OF COLORECTAL AND LIVER TUMORS. AIRC Regional Grant.

Cancer was expected to be one of the human health problems that could benefit from the completion of the human genome information. To address the expectation, this project brings together clinicians and molecular biologists to investigate health problems associated with colorectal and liver cancer. The best known and, so far, most effective instrument to generate genome-wide information has been the use of microarrays for gene expression profiling that, together with the bioinformatic strategies for analyzing microarray data, have allowed to put expression aberrations into a global perspective and allowed to compare pathologic versus normal profiles. Cancer has been analyzed using this technology to define tumor molecular classifications, discover diagnostic methods for the prediction of cancer susceptibility and prediction to drug response. Here, we intend to use this technology for the study colorectal and liver cancer features. In addition, aberrant DNA methylation has proven to be a tumor marker that can be detected with high sensitivity and specificity. Here, we intend to identify a panel of highly informative methylation markers and use them as screening tools for the early diagnosis of colorectal and hepatocellular carcinoma. The project is organized in four interlaced Tasks, each one leaded by one of the participating groups. Each task is defined by specific objectives. The first two tasks involve the oncogenomic classification of colorectal and liver cancer through the use of EST and microRNA microarrays. Their specific objectives are: (i) discovery of gene expression signatures with prognostic significance in colorectal cancer; (ii) integration of EST and micro RNA microarrays, microsatellite and DNA methylation data into a molecular classification of colorectal carcinomas; (iii) identification of gene expression signatures predicting response to preoperative chemoradiation therapy in rectal carcinomas; (iv) identification of expression signatures differentiating cirrhotic liver associated or not associated with hepatocellular carcinoma, with the aim of identifying molecular markers predicting cancer risk in liver cirrhosis; (v) apply the newly discovered markers of cancer risk for the screening of serum of liver cirrhotic patients for the early detection of HCC. The third task involves the use of DNA methylation markers for the early diagnosis of colorectal and liver carcinomas, whose specific objectives are: (i) discovery of new methylation markers; (ii) use of an optimized panel of DNA methylation markers for the follow-up of colorectal and hepatocellular cancer patients; (iii) use of an optimized panel of DNA methylation markers for the screening of colorectal cancer patients’ first-grade relatives and patients with liver cirrhosis. The entire project is supported by a bioinformatic infrastructure (Task 4) for data management, mining and validation of microarray results to define molecular signatures in cancer, whose specific objectives are: (i) storage and management of microarray experiments; (ii) mining of microarray profiles: data normalization, quality control and validation of gene signatures; (iii) communication with clinical data. Through the identification of molecular markers that are able to predict the clinical course of colorectal and liver cancer and the response to preoperative therapeutic regimens in rectal cancer, a significant improvement on patients’ clinical management can be achieved. In addition, by defining the most useful DNA methylation markers and the most effective approaches for their identification in body fluids of colorectal and hepatocellular cancer patients, the project can provide highly sensitive and specific screening instruments, whose application could potentially improve long-term clinical outcome.