February 12, 2018
Age-related declines in the immune system may better explain the increasing incidence of cancer with age than can simply the steady accumulation of genetic mutations. This new finding could affect cancer prevention and treatment, say the investigators.
The research, which was published online in the Proceedings of the National Academy of Sciences of the United States of America on February 5, used a mathematical model to compare age-related changes in the incidence of over 100 cancers with age-related declines in the immune system and found that the model fit very well for more than 50 types of cancer.
The model was a better fit than the traditional model of accumulating genetic mutations and was better able to explain sex differences in the age-related increase in cancer incidence for specific forms of the disease.
Senior author, Thea Newman, PhD, School of Life Sciences, University of Dundee, United Kingdom, said in a release, "This is still very early days but if we are proven right then you could be talking about a whole new way to treat and prevent cancer."
She continued: "Nearly all of the mainstream research into cancer is based on how we can understand genetic mutations, target them and thereby cure the disease.
"We're not debating the fact that mutations cause cancer, but are asking whether mutations alone can account for the rapid rise in cancer incidence with age when ageing causes other profound changes in the body."
Coauthor Clare C. Blackburn, PhD, Medical Research Council Centre for Regenerative Medicine University of Edinburgh, United Kingdom, added: "We believe that our findings are extremely relevant and show the need to take the immune system even more seriously in cancer research."
However, an expert in the field approached for comment questioned the researchers' conclusions, pointing out that they relied on an outdated model of tumorigenesis and that not all cancer incidence rates simply increase with age, as implied by their model.
Cancer Risk Increase With Age
Previous studies have shown that the incidence of cancer increases with age, with a median pivot age (signifying the crossover between a very low to relatively high risk) of 49.9 years across all cancer types.
Moreover, it is known that genetic predisposition and exposure to lifestyle and environmental factors lead to cancer via the accumulation of DNA mutations, with the traditional belief that five to six rare "driver" mutations are required in one cell to initiate cancer, termed the power law model.
Because the incidence of many infectious diseases also increases with age, the researchers hypothesized that the age-related changes in cancer incidence may be better explained by the aging immune system than by solely the accumulation of mutations.
They therefore developed a mathematical model based on two assumptions:
1. That potentially cancerous cells arise with equal probability at any age and
2. That there is an immune escape threshold related to T cell production, above which immunogenic cells can overwhelm the immune system and lead to a clinically detectable disease.
"For our model, we imagined a war between T cells and cancer cells, which the cancer cells win if they grow beyond a certain threshold," said lead author, Sam Palmer, PhD, School of Mathematical and Computer Sciences, Heriot-Watt University Malaysia, Putrajaya.
"We then set this threshold to be declining with age, proportional to T cell production."
The team obtained cancer incidence data from the US Surveillance, Epidemiology, and End Results program on approximately 2 million cases of 101 types of cancer in adults aged 18 to 70 years, as well as data from the Centers for Disease Control and Prevention on bacterial and viral disease incidence.
They initially checked their mathematical model with incidence data for infectious disease, verifying that it fit.
They then showed that, by using a two-factor immune model, 57 cancer types fit very well (R² > 0.95, or a median of 0.956) with their calculations, while only 47 cancers fit a power law model of accumulating genetic mutations (R² > 0.95, or a median of 0.947).
Next, they focused on cancer incidence in males vs females because it has been shown that cancer is 1.33 times more common in men and that the incidence increases more rapidly in men in 70 of the 87 cancers that have sex separation.
The team found that T cell receptor excision circle (TREC) levels, which indicate T cell production, were 1.46 times higher in women than in men and that TREC rates declined faster in men than women.
"The increase of cancer incidence with age is slower in women, something which we would naively expect to be effectively gender-neutral," said study coauthor Luca Albergante, PhD, Institut Curie, Université de Recherche Paris Sciences et Lettres, Paris, France.
"However, the thymus gland shrinks more slowly in women, so we were able to make a prediction on the differential cancer incidence with gender that once again shows our model to be more accurate than the traditional model."
Dr Blackburn added: "In addition to mutations, this suggests we should also focus on how to boost thymus function in a controlled way, perhaps by transplantation or by controlled regeneration, so we can increase the number of T cells we are making."
"Of course, we also need to look at whether there may be unintended consequences of doing this, and how to minimize these if they occur."
Mutations as Key Cause of Cancer
For comment, Medscape Medical News approached Cristian Tomasetti, PhD, from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, who has coauthored several recent papers suggesting that random mutations are responsible for most cancers. Those findings were widely reported in the media as showing that most cancer is "due to bad luck."
Dr Tomasetti said that he does not "consider their study sound."
"The power law does not represent the correct model for tumorigenesis; it is a more than 50-year-old model that captures only some aspects of the tumorigenesis process," he said.
"Therefore, a comparison between their model and the power law does not represent the appropriate analysis to conclude that their model is better at explaining the observed data than the current theory based on the gradual accumulation of somatic mutations."
He added: "With their theory, it is very difficult to explain why for various cancer types the incidence decreases at very old ages."
Dr Tomasetti also noted that a large literature supports the gradual accumulation of cancer mutations as a key cause of cancer.
This work was supported by Scottish Universities Life Sciences Alliance and the National Institutes of Health through a Physical Sciences in Oncology Centres Grant, the Medical Research Council, the European Union Seventh Framework Programme collaborative project ThymiStem, and the Instituts Thé matiques Multi-Organismes Cancer, within the framework of the Plan Cancer 2014– 2019 and convention Biologie des Systè mes BIO2014. The authors have disclosed no relevant financial relationships.
SOURCE: February 12, 2018. Proc Natl Acad Sci U S A. Published online February 5, 2018.