Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Periodic Report Summary 1 - COLONGEVA (Implications of copy number variants of the genome in the etiology and progression of colorectal cancer)

Despite substantial progress has been made in the past decade, colorectal cancer (CRC) is still one of the most devastating diseases in the Western world. Therefore, there is the need for a greater understanding of the genetic basis of CRC progression and the identification of predictive biomarkers to aid selection of patients likely to respond to therapy. The main goal of this project is to decipher the role of genomic mutations and copy number variants (CNVs) in the prognosis and progression of CRC, to better understand which genes, transcripts and molecular pathways are affected in the colorectal tumorigenesis, thus it will have broad health implications and will lead us towards a personalized medicine.

Specifically, this proposal provides insights into the following state-of-the-art research topics:
1- Discovery of copy number variants associated with an increase colorectal cancer susceptibility and progression: The ultimate goal of this translational effort is to identify genomic biomarkers to risk-stratify patients according to prognostic factors. Large structural variants including uniparental disomies and aneuploidies has been assessed in tumor samples and lymphocyte blood DNA of colorectal cancer patients. At this time, biomarkers for tumor recurrence are assessed in stage II colon cancer patients in order to establish those patients that may benefit from adjuvant chemotherapy.
Integrative analysis of SNP-arrays, array CGH and methylation status has led to the identification of unequivocal uniparental disomy profiles that unveil novel candidate tumor suppressor genes using an own sample set as well as a validation set using The Cancer Genome Atlas CRC data. These results were recently published in the peer-reviewed scientific journal Carcinogenesis. A follow-up study aims at deciphering whether the presence of mosaic uniparental disomies in lymphocyte blood DNA may indicate the presence of germline structural alterations with a causative role in the tumorigenesis.

2- Genomic alterations and mutations in radiochemotherapy resistant CRC tumors: The integration of copy number alterations, whole-exome sequencing, and gene expression in spatially separated multiple primary tumors and their corresponding metastasis before and after being chemotherapeutically treated will define genetic markers that drive tumors to become resistant to chemotherapeutic agents. Whether these tumors become resistant over time or an existing clone with molecular features prone to resistance already exists in the primary tumor is still a matter of debate. Furthermore, multi-resistant metastatic colorectal tumors evade second and third line of treatments with targeted therapies. Intriguingly, we have identified that the nuclear localization of the insulin growth factor 1 receptor (IGF-1R) is associated with progression-free survival and overall survival after treating CRC patients with first line of chemotherapeutic agents as well as targeted therapies (e.g., ganitumab), thus suggesting that nuclear IGF-1R is a surrogate for resistance to treatment. (Codony-Servat J et al., manuscript under preparation)

3- Mechanisms of formation of genomic alterations at the sites of CNVs. The emerging field of the nuclear organization highlights that
structure-function relationships need to be explored at all levels from molecules to the entire system. The main goal of this research is to understand how the higher order of chromatin organization and the nuclear architecture influence the formation of CNV, which ultimately will result in cellular advantages for the tumor cell.
Using an in vitro model of isogenic cell lines, we encountered that polyploid cells have increased levels of replication stress causing DNA damage, lagging chromosomes and aberrant mitosis. Thus, our data demonstrate that whole genome duplication induces high levels of genomic instability, which will fuel the ongoing levels of intratumoral heterogeneity observed in cancer specimens. (Wangsa D et al., manuscript under preparation)

My research group works under the umbrella of Dr. Antoni Castells, head of the Gastrointestinal and Pancreatic Oncology Group and the Gastrointestinal Department of the Hospital Clínic of Barcelona. Nevertheless, my path to independence is corroborated by the fact that I am principal investigator in two official grants, and I am supervising the doctoral thesis of four PhD students. Moreover, being awarded with a Miguel Servet position early 2014 provided me with the possibility to hire a research technician for my own group.

Reported by



Life Sciences