Largest ever genetic analysis of colorectal cancer reveals DNA damage caused by tobacco and gut bacteria
The mutational signature SBS93 — which may be linked to smoking and alcohol consumption — was found in one in three tumors
Life may depend on a single letter. A person is made up of some 30 trillion cells, which act as a team with inconceivable synchronization. Each type of cell — neuron in the brain, red blood cell in the blood, enterocyte in the intestine — performs its function thanks to a DNA manual inside it, written with some 3 billion letters (ATGGCGAGT…). Each letter is simply the initial of a chemical compound with different amounts of carbon, hydrogen, oxygen and nitrogen. T is thymine (C₅H₆N₂O₂). G is guanine (C₅H₅N₅O). A change in one of these letters is enough for the cell to become cancerous and spread. Just colorectal cancer — often arising from a runaway enterocyte — causes the death of almost a million people each year worldwide. On Wednesday, the largest genetic study ever conducted on this tumor revealed its fatal DNA errors.
The authors analyzed the complete genome, letter by letter, of more than 2,000 colon and rectal cancers from patients in the 100,000 Genomes Project, a British initiative to read the DNA of cancer cells or cells with rare diseases. Computational biologist Claudia Arnedo, 30, participated in the work. “We have been able to describe the most complete set of mutational signatures in colorectal cancer to date,” she says. Mutational signatures are alterations in the sequence of letters, caused by a specific mechanism. For example, the so-called SBS4 (single base substitution) is caused by tobacco consumption.
Arnedo — who was formerly at the Barcelona Institute for Biomedical Research and now works at the University of Cambridge — explains that around 100 mutational signatures have been identified, most of unknown origin. The new study has revealed the importance of SBS93, characterized by changes of a T (C₅H₆N₂O₂) to a C (C₄H₅N₃O) and of a T to a G (C₅H₅N₅O). “SBS93 has previously been associated with esophageal and stomach cancers, but its cause is unknown. In our study, we found that SBS93 is one of the most common mutational signatures in colon cancer, specifically in those tumors with microsatellite stability, which are the most frequent,” says Arnedo.
SBS93 appeared in one in three tumors analyzed, especially in tumors diagnosed at a younger age. “We still do not know the mechanism that causes it, but we have identified that it tends to occur together with other mutational signatures, including some of those that have been associated with alcohol and tobacco consumption, which suggests that SBS93 may have a similar origin,” says the scientist.
Geneticist Ian Tomlinson led the research from Oxford University in the United Kingdom. The researchers identified more than 250 genes that harbor mutations that cause colorectal cancer, thanks to the use of various computational methods. Some of these methods were developed by the team led by biologist Núria López Bigas at the Institute of Biomedical Research of Barcelona. Fifty of these genes had not been linked to cancer until now. The results were published on Wednesday in the prestigious journal Nature.
Bacteria living in the human digestive system are linked to genetic alterations that cause cancer. This was demonstrated by Spanish biotechnologist Cayetano Pleguezuelos and his colleagues at the Hubrecht Institute in the Netherlands, in a study published in February 2020. The researchers observed that a specific strain of the bacteria Escherichia coli produces a toxic molecule, called colibactin, which damages the DNA of human cells. The new work has found mutations caused by this microbe in 13% of the cancers analyzed. A diet rich in fiber (fruits, vegetables, legumes, cereals) and low in processed meats helps to ensure a healthy community of intestinal bacteria.
Biologist José Tubío, from the University of Santiago de Compostela, praises the study, in which he did not participate. “Such a large number of tumors had never been processed. This has allowed us to detect mutated genes that seem to be associated with the disease and that had not appeared in previous studies because they are much less frequent,” he says. “This is precision oncology: identifying all mutations, even if they are very rare, in order to try to design specific drugs in the future or boost the immune system to be able to deal with these tumors,” adds Tubío, who in 2020 collaborated in the historic analysis of more than 2,600 genomes of 38 different types of cancer, published by an international consortium.
The new results confirm that the tobacco industry is the number one enemy of global public health, as warned by the doctor Elisabete Weiderpass, director of the International Agency for Research on Cancer, in an interview with EL PAÍS. “It is the industry of death. Death is its product. Half of the people who pay for their products die. They sell death,” she said.
José Tubío is urging authorities to “apply much more drastic preventive measures, such as prohibiting tobacco for the new generations of young people.” In April, the United Kingdom approved a law that will prohibit the sale of tobacco to people born after 2008, starting from 2027. In the U.K., 13% of the population smokes. In Spain, the figure is 22%.
Colorectal cancer is the third most common type of cancer and the second most common cause of death in the world, after lung cancer. Thanks to medical advances, the five-year survival rate has now reached 65%. In recent years, the incidence of colorectal cancer has been mysteriously increasing in people under 50, at an alarming rate of 3% each year in many countries. The main suspects are obesity, a sedentary lifestyle and sugary drinks.
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