Could chance be involved in the process of tumorigenesis?

A tumor or a neoplasm is the result of an excessive and uncontrolled proliferation of a single normal cell, which has been transformed into a cancerous state following multiple cellular alterations and rendered resistant to apoptosis, cell-to-cell contact inhibition, growth factor removal or immune cells (J.S. Bertram, 2000). According to the latest figures from the World Health Organization, cancer is responsible for 13% of deaths worldwide with approximately 8 million deaths a year and at least 14 million new cases diagnosed every year. The appearance of a malignant tumor is associated with multiple interrelated factors relevant to the subject itself (heredity, hormonal state, efficacy of immune defenses), but also to its environment (life conditions, alimentary habits, exposition to diverse toxic or infectious agents). Smoking is for example a well known risk factor for lung cancer causation while similarly; ultra-violet radiation from sunlight is strongly linked with melanoma, a common form of skin cancer (G.B. Ivry et al., 2006). Obesity was shown, by numerous epidemiological studies, to be associated with the development of cancers in a variety of tissues such as the esophagus, colon, kidney, breast, pancreas, liver or gall bladder (E.E. Calle et al., 2004). Researchers also demonstrated that almost 16% of cancer cases are directly and indirectly caused by a chronic infection with the likes of human papillomavirus in 98% of cases of cervical cancers, hepatitis B virus in some hepatocarcinoma, as well as Epstein Barr virus having a possible involvement in at least four different types of cancer including Burkitt’s lymphoma and nasopharyngeal carcinoma (J.K. Oh et al., 2014).

Each cell of the organism undergoes the duplication of its genomic content during the cell cycle before continuing its division process. Each of the four phases (G1, S, G2 and M) of the cell cycle contains checkpoints required to ensure the integrity of the genetic material and which allows the cell to either go along with the division process following the repair of any DNA damage or undergo programmed cell death if the damage is simply too important. Spontaneous DNA damage during normal cell division can, however, lead to cancer as the risk of mutation cannot be driven down to zero even by inheriting an immaculate genome and/or avoiding all known mutagens. In spite of several cell divisions occurring throughout life, the development of a cancer cell remains a relatively rare event, mainly because of the need for multiple alterations to acquire the malignant phenotype. The number of alterations for a cell to become neoplastic is thought to be strictly tumor-dependent. However, this level can be correlated with increasing age and it is generally believed that at least five to six genetic hits are a pre-requisite for the formation of solid tumors in humans, and that genetic alterations other than mutations can also transform cells such as translocation, amplification or loss of heterozygosity (Cahill et al., 1999). Since mutations can only come about during cell division, the number of cell divisions a specific cell type undergoes during someone’s life correlates directly with risk of developing cancer. In other words, tissues rich in dividing stem cells (e.g. intestinal tissue) are more prone to tumorigenesis than tissues poor in dividing stem cells (e.g. cardiac tissue).

Keeping this observation in mind, Dr. Tomasetti and Dr. Vogelstein from Johns Hopkins University conducted a study to discover the reasons behind the variations in cancer risks. To that effect, they pooled published information on 31 different tissue types, estimated the number of stem cell divisions over a lifetime and plotted the total number of stem cell divisions against the likelihood of developing a cancer to look for correlations. In parallel, they looked at the contribution of environmental factors and inherited mutations on lifetime cancer risk; thus creating two groups with one affected by the environment and genetic factors and one comparatively unaffected. The environment and other genetic factors could explain 35% of cancers. Conversely, the researchers determined that 65% of the differences in cancer risk across tissue type were linked with the number of stem cell divisions in those tissues. Stem cell divisions cannot be controlled and were therefore referred to as the “chance element” or “bad luck” by the authors.

These observations generated big headlines in the news and much controversy amongst cancer biologists and clinicians. One reason was that two of the most common cancers, namely prostate and breast cancers, were not including in this analysis. It did not take into account country specificities with significantly different prevalence of some forms of cancer in different parts of the world. Standard deviations around these values were wide with intervals ranging from 39% to 81%, therefore reducing their significance and the scientists’ confidence in their precision. The work was also based on past studies estimating both the lifetime risk of developing cancer and the number of stem cell divisions for different tissues. Any bias in these studies would seriously undermine the validity of these calculations and the resulting outcome. Last but not the least, scientists argued that these data could easily be misinterpreted and that the term “bad luck”, which is associated with a sense of ineluctability, could negate the efforts made around the world in promoting a healthy lifestyle in the fight against cancer. Dr. Tomasetti and Dr. Vogelstein did not try to determine why some people get cancer while others do not; but rather tried to decipher why some types of cancer are more common than others. Despite the comments, this study led to a better understanding of the disease and could potentially help with the design of new strategies focusing on the most common types of cancer and on limiting mortality. Most importantly, it conveyed the message that cancer patients should not blame themselves for it. The approach remains an interesting one and corroboration with further studies could indicate the participation of chance in the process of tumorigenesis.

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