What Selection Pressure Does to Mutations Favoring Cancer? Highlights of A Simulation Approach
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 10, Issue 4
Abstract
Context: research in oncogenetics has focused for years on mutations increasing independently the risk of cancer (ex. BRCA mutations for breast/ovarian cancers). Nowadays, interactions between mutated genes are searched for. Besides, because deleterious mutations shorten life and thus reproduction outcomes, why have they not been eliminated by selection pressure? Methods: we developed software to test various hypotheses about mutations survival among a theoretical population having main demographic characteristics of a primitive population. Various simulations (Monte-Carlo approach) with various genotypes tested how several deleterious mutated genes with various penetrances could interact and possibly survive despite the life shortening they induce. Results: simulation over millennia showed that deleterious mutations needed to provide evolutionary compensations such as higher fertility and/or earlier onset of reproductive capacities. This las characteristic was a strong factor enabling deleterious mutations to last. Because in female, menopause terminates the fertility period, iterations tended to select spontaneously mutations favoring cancer after menopause, without any consideration about hormonal exposure. Interactions between highly penetrant mutations were very unlikely to last and tended to split apart populations carrying each different mutation. Some results regarding fertility were validated using our database of 9000 pedigrees at high cancer risk. Very penetrant germline (hereditary) mutations in Human are scarce [1] and reports of de novo mutations are quite rare [2,3]. Even if this statistic is not exactly right, this means that mutations favoring cancer like BRCA1 and BRCA2 are very uncommon events in human's history and it is very likely that present known mutations are quite old (several millennia). Other etiologic hypotheses concerning hereditary cancer risk suggest possible interactions between several weakly penetrant mutations. Whatever the penetrance, these deleterious mutations have a direct impact on life expectancy of carriers (it shortens life time because of diseases that they favor at early ages). One might ask why natural selection, generation after generation, did not eliminate them. This is the issue of this article. To answer this question, the first paragraph describes the methods we used, the population parameter that were necessary, and how they were mixed together to provide an acceptable population-size evolution. The characteristics of the mutations that are introduced in the model are in accordance with the knowledge about BRCA mutations. A stochastic computer routine was developed to simulate what happens along generations to these mutations. First tests concerned the introduction of 5 mutations favoring cancer at different ages that do not provide any specific advantage about fertility. Second tests used various but relevant corrective measures to counterbalance the natural decline of mutations rate among studied population. In a second paragraph, these results are discussed in the light of what is known about BRCA mutations. Observational results are then described: they were obtained from a large database of family presenting with a hereditary cancer risk (more than 9 000 families and 190 000 family members recruited since 1985 in Centre Jean Perrin Oncogenetic Department). Limitations and further possibilities are described in the last chapter.
Authors and Affiliations
Kwiatkowski Fabrice, Serlet Laurent, Bignon Yves Jean
Keywords
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- EP ID EP588419
- DOI 10.26717/BJSTR.2018.10.001989
- Views 130
- Downloads 0
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