Populations living in extremely cold or high altitude environments have genes that increase survival but also predispose people to cancer in life, especially to the lungs, breast and colorectal cancer, according to the researchers.
Data analysis of the GLOBOCAN-2012 global cancer incidence survey shows that evolutionary adaptation to environments of extreme or prolonged cold produces genetic variants that interfere with tumor suppression and increase vulnerability to almost all cancers.
"This is the first study to provide evidence that a high risk of cancer may be the result of evolutionary adaptation in certain environmental conditions," says Konstantinos Voskarides, PhD, of the School of Medicine. from the University of Cyprus in Nicosia, and colleagues.  Notably, the findings support a "long-standing hypothesis for cancer" known as antagonistic pleiotropy, say the authors in their report, published online Dec. 5 in Molecular Biology and Evolution.
In this theory of evolution centered on the gene, genetic variants that predispose to a disease can undergo natural selection when they offer a survival advantage. The theory was proposed in 1957 by the American evolutionary biologist George C. Williams, PhD, as an explanation for senescence.
"Cellular resistance at low temperatures and at high altitudes probably increases the likelihood of malignancy," the study authors write. "This effect can hardly be filtered by natural selection since most cancers appear later in age after most people have children."
A separate analysis revealed a special selection for tumor suppressor genes. This finding supports the results of previous functional studies that show that reduced apoptosis – or programmed cell death – is beneficial in extremely cold and high altitude environments, but is caused by variants of the p53 tumor protein, which is responsible for suppression of the tumor, say the researchers.
These findings could change the way that most doctors and scientists think about the origins of cancer, said Dr. Voskarides Medscape Medical News.
"Most doctors and biologists believe that somatic mutation is all in the genetics of cancer," he said.
"That's not true," he said.
"Genetic predisposition is an important factor in cancer, and we have to pay more attention to this," he continued. "Evolutionary theory can explain the molecular mechanisms of human disease and reveal unknown epidemiological phenomena," he said.
When asked if he thought that most cancers might be related to the phenomenon of pleiotropy antagonist, Dr. Voskarides said: "I think it is very possible. This is due to the fact that most cancers have an important genetic parameter that is affected by natural selection events. "
The results of his own research indicate that tumor suppressor genes may play a more important role than oncogenes in the development of cancer and could potentially be a new therapeutic target, said Dr. Voskarides.
Focusing on extremely cold environments
In addition to data from the GLOBOCAN-2012 survey, Dr. Voskarides and his colleagues examined data from 254 cancer genome association studies (GWAS) and from 186 human populations. By focusing on the effect of low temperatures in Arctic / Scandinavian climates or high-altitude populations, they discovered that the seven GWAS that identify the genes selected to live in extreme cold conditions included Greenlandic Eskimos, Siberian Eskimos, and Amerindians.  The association between cancer rates and extreme cold environments was strongest among Native Americans, a population in which the most important associations with colorectal cancer were found. It was discovered that Siberian Eskimos have the most significant association with genes selected for colorectal and esophageal cancer, as well as for lung cancer, head and neck cancer, breast cancer, bladder cancer, hepatocellular carcinoma and lymphoma.
The most frequent The BRCA1 mutation worldwide was found in Inuit peoples living in Greenland.
Genes selected to live at high altitudes were identified in Tibetans, Andeans and Ethiopians. The largest cancer associations were observed in populations living in the Andes and the Himalayas.
It was discovered that Andeans and Tibetans had adaptive genetic variants that were highly associated with a long list of cancers, including lung cancer. The researchers note that a 2016 study showed that EGLN1 – the gene under selection in high altitude environments – predisposes to lung cancer in Tibetans.
Other cancers associated with genes under selection in the Andean-Tibetan group including cancer of the esophagus, cancer of the head and neck, squamous cell carcinoma, stomach cancer, breast cancer, melanoma, Hodgkin's disease, neoplasms of the mouth, pharyngeal neoplasms, nasopharyngeal neoplasms, lymphoblastic leukemia of precursor cells, adenoma, colorectal cancer, cervical uterine neoplasms, mesothelioma, pleural neoplasms, laryngeal neoplasia and prostate cancer.
It was found that the Oromi in Ethiopia had the most significant associations with chronic myelogenous leukemia, acute lymphoblastic leukemia and myeloid leukemia.
"These data show that these populations exhibit extremely high levels of cancer incidence, especially for lung, breast and colorectal cancers," Dr. Voskarides said in a statement.  "It seems that the populations [are] segregated under the concept of extreme environment – extreme risk of cancer".
This study may also shed light on the geographic distribution of cancer and help explain why cancer incidence and mortality rates are higher in some populations in specific geographic areas compared to populations living elsewhere, say the authors of the study.
"Today there is limited information on the factors that determine this spatial distribution," they point out. "The environmental and genetic factors are equally suspect, since in multifactorial diseases, environmental variables and genetic variants make up the risk per population".
The next steps in this research include investigating specific genetic variants in tumor suppressor genes that are under selection and selection of specific genes to inhibit cancer development, said Dr. Voskarides.
The authors have not disclosed any relevant financial relationship.
Mol Biol Evol. Published online on December 5, 2017.
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