Identified 20 genetic causes of common cancers - The País.com (Spain)

All cancers are caused by somatic mutations: genetic alterations usually not inherited, but have occurred in individual cells throughout life. A crucial issue is to understand what causes these mutations, and international scientific consortium gives today a big step to identify 20 mutational signatures different in human cancers. Each represents a type of mechanism responsible for generating genetic alterations and knowledge “reveals the diversity of mutational processes underlying the development of cancer”, according to scientists, and has implications for the prevention and treatment of this health scourge.

Some of these

signatures , or mutational processes, are present in many cancers, and others are specific to a class or other tumor. Furthermore, some of these mechanisms of genetic alteration are due to age, other systems defects in genome maintenance and repair, and other environmental mutagens as a snuff (in the lung) or ultraviolet light (in cancer skin). The data also revealed in many cancers small regions of DNA that hypermutation suffer a much higher degree of disturbance to the rest of the genome.

Some mutational processes are shared by many tumors

The consortium involves researchers from 14 countries and was coordinated by Michael Stratton and his colleagues at the Sanger Institute in Hinxton, UK. The Spanish contribution is led by Elias Campo, Hospital Clínic-IDIBAPS and University of Barcelona, ??and Carlos Lopez-Otin, Institute of Oncology, University of Oviedo. This is a comprehensive work that scientists have analyzed the genome of 7,042 tumors of all types, which together contain no less than 5 million mutations.

Total . The Spanish Society of Medical Oncology (SEOM) indicates that each year nearly 200,000 diagnosed cancers in Spain (specifically, their estimates are 196 902 cases), and collected just over 100,000 deaths (104 156). The figures do not include nonmelanoma skin.

Colorectal . is the most frequent: 28,551 per year, with a mortality of about half.

Prostate . is the second in incidence: 25,231 cases a year, with 6,000 deaths annually.

Lung . It affects about 23,000 people a year, most (approximately 85% of total), men.

Mama . 22,000 are diagnosed annually, and die of it about 6,000 people.

Bladder . is, in absolute terms, the fifth in incidence: 13,008 cases per year, with a mortality of 4,820 people a year.

By gender . Of the total, 60% occur in men and 40% in women, although the difference between the sexes is reduced gradually each year.

With those numbers, it is truly remarkable that they have been able to reduce the mechanisms responsible for only those 20 mutational signatures different. In fact, some types of cancer have only two signatures, which implies that there are only two mutational mechanisms involved in their genesis. Other more complex tumors come to display up to six firms. In total, scientists have examined the 30 most common cancers.

A good example of how the work is distributed between the consortium is the Spanish contribution, which has focused on a hundred genomes of a particular type of cancer, chronic lymphocytic leukemia. The results showed that the tumor of blood cells is generated by two basic processes, one due to aging and other deficiencies in DNA repair mechanisms. As damage to the genetic material are constant throughout life, our survival actually depends on the continuous action of these processes of repair and genome maintenance, when they fail, spontaneous mutations accumulate with fatal results.

“Without the international collaboration of all working groups involved in the project,” says Lopez-Otin, “would have been impossible to obtain these important results.” Field added: “This is one of the first examples of the new vision that can deliver the massive sequencing genomes and coordinated through the International Consortium Cancer Genome”. In these times of budgetary stinginess, it is fair to add that the Spanish part of the project has been funded by the Ministry of Economy.

One of the most peculiar phenomena which revealed international work are small areas of the genome that suffer some abnormally high mutation rates (hypermutation). Scientists have dubbed the kataegis , for the Greek word for storm. It is not that chromosomes break or shuffle: mutations that occur there are so punctual (letter changes of DNA by another) as those occurring in the rest of the genome, only occur at a rate stormy : to many thousands of mutations in a small space.

Although kataegis , or storms mutations themselves do not consist in chromosomal breaks, it does often occur in the vicinity of one of them. Specific areas where they occur-both as chromosomal rearrangement mutations storm-are quite reproducible in each type of cancer, but vary between types. The kataegis are common in breast cancer (which in fact were discovered), pancreas, lung, liver, medulloblastoma, lymphoma and B cell acute lymphoblastic leukemia.

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phenomenon storms vaguely similar to mutation occurs during the normal maturation of the lymphocytes, the white blood cells which produce antibodies and other specialized proteins in the body recognize foreign agents. Since these pathogens are potentially infinite, the antibody genes using a variety of mechanisms to generate a range specificities indefinite equally and hypermutation-controlled and restricted to certain very specific areas of the gene, is one of its main resources. Indeed, kataegis in lymphocytes cancers such as lymphomas, tend to occur in the immunoglobulin gene, the components of the antibodies. In other cancers not, however.

“is more likely to be discovered mutational signatures” Stratton and colleagues recognize in the main article on the subject in Nature , “with a precise definition of their characteristics, as the number cancers sequenced genomes increases and refining analytical methods go “. Scientists claim to have found all of the processes responsible for cancer mutations, although they believe they have most of them.