Cancer is linked for the first time with an alteration in the protection of chromosomes

The research has been led by the researchers Elías Campo, from the Faculty of Medicine of the UB, the Hospital Clínic of Barcelona and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Carlos López-Otín, from the Institute of Oncology of the University of Oviedo, and Maria Blasco, director of the Spanish National Cancer Research Center (CNIO). It means a new advance of the Spanish Consortium Genome for the Study of the Genome of Chronic Lymphocytic Leukemia (CLL Genome).

The chronic lymphatic leukemia is the most common type of leukemia in Western countries. Once the most common development genetic and epigenetic changes have been deciphered, it is necessary to understand the biochemical mechanisms altered by these changes, in order to improve the diagnosis and treatment of this disease. Thus, taking into account the previous research carried out during the last two years, the researchers focused on the mutations that affect POT1 gene, one of the genes involved in the protection of the edges of the chromosomes, the telomeres. It is the first time that a gene with this function appears mutated in a human cancer. According to the researchers, “the biology of the telomeres has been studied for a long time as alterations to their maintenance are associated to cancer and aging”. Although some mechanisms by means of which tumorous cells alter their telomeres are known, mutations in POT1 reveal a previously-unknown route.

Each chromosome has on its edges, in the telomeres, a protective cover formed by proteins, and POT1 is the staple that locks it into place by joining it to the telomeric DNA. The mutations found on POT1 prevent this gene from carrying out its function. Therefore, the DNA of the edge of the chromosome does not have its protective cover. The research of the biochemical route that leads from these anomalies to the uncontrolled growth of B cells may shed light on key aspects of the chronic lymphatic leukemia and on cancer in general.

One of the most frequently mutated genes in leukemia

Moreover, after having analyzed the genome of 341 patients of chronic lymphatic leukemia, comparing in each case the genes of healthy cells and tumorous cells, researchers discovered that POT1 is one of the most frequently-mutated genes in this disease.

Previous results obtained by CLL Genome had already proved that thousands of mutations are involved in this disease, and that each patient presents a unique combination of hundreds of them. One of the most significant findings of the studies of the Consortium is the great genetic and molecular diversity of the disease. Mutated genes identify relatively small sub-groups of patients with different characteristics in their disease. In fact, the most-repeated mutations are only found in 15 % of the patients. Nevertheless, its identification is a considerable breakthrough, since it is a step towards personalized treatment, based on the genetic profile of each tumor.

In the work published, researchers found that 3.5 % of chronic lymphatic leukemia patients present mutations in POT1, but this figure rises to 9 % in those patients who suffer a notably aggressive form of the disease. Thus, the study identifies POT1 as one of the most important genes for this disease. Campo concludes that “patients with mutations in POT1 belong to the group with the grimmest prognosis. Thus, a therapeutic intervention that follows this route may help the treatment of a group of patients whose clinical perspectives are, currently, very unfavorable”.

CLL Genome is funded by the Ministry of Economy and Competiveness through the Carlos III Health Institute, and is part of the International Cancer Genome Consortium (ICGC). Three years ago, the journal Nature highlighted the potential relevance of the results expected by ICGC for the development of new methods of diagnosis and therapies against cancer, as the Consortium plans to coordinate in a global scale the sequencing and the analysis of more than 500 tumorous genomes of each of the 50 most-frequent types of cancer. Since then, Nature and Nature Genetics have published several articles that show the advances made by the Spanish researchers who collaborate in ICGC, based on the analysis of the genomic and epigenomic alterations of more than 100 patients of chronic lymphatic leukemia. The new research published by Nature Genetics goes deeper in one of the most outstanding discoveries derived from these early studies, and contributes to emphasize the relevance of the dynamics of the telomeres, decisive structures for a better understanding of processes as complex as cancer and aging.

The Spanish contribution to this international consortium combines the work of more than twelve institutions: the University of Barcelona, the Hospital Clínic of Barcelona, IDIBAPS and the Catalan Institute of Oncology, all centres affiliated with the HUBc, the health campus of the UB. Other collaborating institutions are: the Institute of Oncology of the University of Oviedo, the Center for Genomic Regulation of Barcelona, the Center for Cancer Research of Salamanca, the National DNA Bank, the Spanish National Cancer Research Center, the University of Deusto, the University of Santiago de Compostela, the Barcelona Supercomputing Center (located at the Barcelona Knowledge Campus, BKC), and the Center for Genomic Analysis.

Article:

A. J. Ramsay, V. Quesada, M. Foronda, L. Conde, A. Martínez-Trillos, N. Villamor, D. Rodríguez, A. Kwarciak, C. Garabaya, M. Gallardo, M. López-Guerra, A. López-Guillermo, X. S Puente, M. A. Blasco, E. Campo and C. López-Otín. "POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia". Nature Genetics, 2013. doi:10.1038/ng.2584