Populations living in extremely cold or high-altitude environments have genes that boost survival but that also predispose individuals to cancer later in life, especially lung, breast, and colorectal cancer, according to researchers.
Analysis of data from the GLOBOCAN-2012 survey of worldwide cancer incidence 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 that provides evidence that high cancer risk may be a result of evolutionary adaptation in certain environmental conditions,” note Konstantinos Voskarides, PhD, of the University of Cyprus Medical School in Nicosia, and colleagues.
Notably, the findings support a “long-standing hypothesis for cancer” known as antagonistic pleiotropy, the authors say in their report, published online December 5 in Molecular Biology and Evolution.
In this gene-centered theory of evolution, genetic variants that predispose to a disease may undergo natural selection when they offer a survival advantage. The theory was proposed in 1957 by US evolutionary biologist George C. Williams, PhD, as an explanation for senescence.
“Cell resistance at low temperatures and at high altitude probably increases the probability for malignancy,” the study authors write. “This effect hardly could be filtered out by natural selection since most cancers appear later on in age after most people have their children.”
A separate analysis revealed special selection for tumor suppressor genes. This finding supports results from 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 tumor protein p53, which is responsible for tumor suppression, the researchers say.
These findings could potentially change the way most clinicians and scientists think about the origins of cancer, Dr Voskarides told Medscape Medical News.
“Most clinicians and biologists believe that somatic mutation is everything in cancer genetics,” he commented.
“That’s not true,” he said.
“Genetic predisposition is a significant factor in cancer, and we have to pay more attention to this,” he continued. “Evolutionary theory can explain molecular mechanisms of human disease and reveal unknown epidemiological phenomena,” he said.
When asked if he thought most cancers could be related to the antagonistic pleiotropy phenomenon, Dr Voskarides said, “I believe 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.”
Results from his own research indicate that tumor suppressor genes may play a more important role than oncogenes in cancer development and could potentially provide a new therapeutic target, Dr Voskarides said.
Focusing on Extremely Cold Environments
In addition to data from the GLOBOCAN-2012 survey, Dr Voskarides and colleagues examined data from 254 cancer genome-wide association studies (GWAS) and from 186 human populations. By focusing on the effect of low temperatures within arctic/Scandinavian climates or in populations living at high altitude, they found that the seven GWAS that identify genes under selection for living in extreme cold included Greenlandic Inuit, Siberian Eskimos, and Native Americans.
The association between cancer rates and environments of extreme cold was strongest in Native Americans, a population in which the most significant associations with colorectal cancer were found. Siberian Eskimos were found to have the most significant association with genes under selection for colorectal and esophagheal cancer, as well as for lung cancer, head and neck cancer, breast cancer, bladder cancer, hepatocellular carcinoma, and lymphoma.
The most frequent BRCA1 mutation worldwide was found in Inuit peoples living in Greenland.
Genes under selection for living at high altitude were identified in Tibetans, Andeans, and Ethiopians. The highest cancer associations were observed in populations living in the Andes and the Himalayas.
Andeans and Tibetans were found to have adaptive genetic variants that were highly associated with a long list of cancers, including lung cancer. The researchers note that a 2016 study demonstrated that EGLN1 ― the gene under selection in high-altitude environments ― predisposes for lung cancer in Tibetans.
Other cancers associated with genes under selection in the Andean-Tibetan group included esophageal cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, breast cancer, melanoma, Hodgkin’s disease, mouth neoplasms, pharyngeal neoplasms, nasopharyngeal neoplasms, precursor cell lymphoblastic leukemia, adenoma, colorectal cancer, uterine cervical neoplasms, mesothelioma, pleural neoplasms, laryngeal neoplasm, and prostate cancer.
The Oromi in Ethiopia were found to have the most significant associations with chronic myelogenous leukemia, acute lymphoblastic leukemia, and myeloid leukemia.
“These data show that these populations exhibit extremely high cancer incidence, especially for lung, breast, and colorectal cancer,” said Dr Voskarides in a statement.
“It seems that the populations [are] segregated under the concept of extreme environment ― extreme cancer risk.”
This study may also shed light on the geographic distribution of cancer and help to explain why cancer incidence and mortality rates are higher in some populations in specific geographic areas compared to populations living elsewhere, the study authors say.
“There is limited information today about the factors that determine this spatial distribution,” they point out. “Environmental and genetic factors are equally suspected, since in multifactorial diseases, environmental variables and gene variants shape the risk per population.”
The next steps in this research include investigating specific genetic variants in tumor suppressor genes that are under selection and targeting specific genes to inhibit cancer development, said Dr Voskarides.
The authors have disclosed no relevant financial relationships.
Mol Biol Evol. Published online December 5, 2017.
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