The below essay by Andriy Marusyk provides a commentary to a recent article by Wong, et al. pertaining to the mechanisms of chemo/radio and therapy induced cancers. Prevailing views explain therapy-induced cancers by postulating induction of new driver mutations.  Whereas several previous reports have challenged this mutation centric view, the article by Wong, et al. is the first report that strongly implies increased selection for p53 mutant clones in secondary malignancies induced by radiation/chemotherapy in clinics.

Cancer evolution: selection matters

By Andriy Marusyk 

Cancers arise and progress because of the underlying somatic clonal evolution. In principle, the process should follow the same Darwinian logic as evolution in natural populations, i.e. genetic mutations and stable epigenetic alterations generate diversity in heritable phenotypes, whereas context-specific selection pressures lead to outgrowth of sub-populations with higher fitness. However, the discovery that clinical progression is associated with recurrent “driver” mutations as well as the observation that some of these mutations can have dramatic phenotypic consequences in experimental models have led to the dominance of mutation-centric paradigms among cancer biologists. Occurrence of “driver” mutations is considered to be both necessary and sufficient for the evolution to unfold, whereas considerations of context-dependence of fitness are usually ignored. Therefore, whenever increased risk of cancer is observed in a context of elevated mutation rates, the link is explained through increased probability of occurrence of “driver” mutations and no further investigation is deemed necessary.

In this regard, elevated cancer risk due to exposure to irradiation and gene-toxic therapies is often used as a poster child for mutation-centric argument while consideration of additional mechanisms is deemed unnecessary. On the other hand, effects of irradiation and chemotherapy are certainly not limited to the introduction of new mutations.  It has been proposed that cytotoxic and growth inhibitory contexts associated with these therapies can lead to selection of pre-existing mutant clones that are less likely to undergo apoptosis or cell cycle arrest 1. Moreover, experimental studies in mouse models have demonstrated that while loss of TP53, the most commonly mutated tumor suppressor, is selectively neutral in context of normal hematopoietic tissue, p53 mutant clones get a clear fitness edge over wild type cells following exposure to ionizing irradiation 2, 3. Still, the relevance of these arguments and findings toward human cancers had remained unclear until of late.

A recent study from Richard Wilson’s lab in Washington University (Wong et al. 4) provides very strong evidence that the link between irradiation and chemotherapy-induced secondary malignancies might be caused by changes of selective pressures rather than induction of new mutations as is commonly assumed. The authors have analyzed mutational spectrum of therapy-related acute myeloid leukemias (t-AML), a blood malignancy commonly associated with chemo and radio-therapy. Contrary to the widely held assumption, t-AML cases displayed no increase in single nucleotide mutations, deletion or insertions compared to spontaneous cases of AML. Instead, the analyzed t-AML cases differed in spectra of recurrent mutations, including elevated incidence of clonal p53 mutations. Together, these findings implicated differences in selective pressures rather than mutation rates. Several lines of evidence supported this implication. First, p53 mutant clones have been detected in hematopoietic system of healthy individuals not exposed to chemo or radio-therapy in about 50% of examined cases (real incidence can be substantially higher given the limited sensitivity threshold), thus suggesting that loss of p53 function does not provide a fitness benefit under normal conditions. Second, analysis of blood samples collected prior to the development of t-AML revealed that expansion of p53 mutant clones preceded the acquisition of additional driver events. Finally, the authors have observed that chemotherapy increases selection of p53 mutant clones in experimental mouse models. Whereas direct demonstration of causality in primary human cancers is next to impossible, the study provides a very compelling argument for the importance of selection of p53 mutant clones rather than elevation of mutation rates in etiology of treatment associated malignancies.

Implications of the study by Wong et al. go beyond t-AML, as many other contexts of cancer predisposition, traditionally explained through elevation of mutation rates, can involve changes in selective pressures favoring the expansion of mutant clones. A few examples of such contexts are aging, smoking, exposure to environmental toxins, diet, inflammation, etc. Whereas consideration of context-specific selective pressures increases the complexity of concepts and adds additional challenges to mathematical modeling, it might be good news from a therapeutic standpoint. Once sporadic mutation has happened, it cannot be “undone”. However, context-specific expansion of mutant clones can potentially be limited or prevented by modifying the context.  Obviously, any therapeutic development in this area would require elucidation of the mechanisms behind changes of selective pressures, but recognition of the role of selection in tumor evolution is a necessary first step.

1.         Blagosklonny, M.V. Oncogenic resistance to growth-limiting conditions. Nat Rev Cancer 2, 221-5 (2002).

2.         Bondar, T. & Medzhitov, R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309-22 (2010).

3.         Marusyk, A., Porter, C.C., Zaberezhnyy, V. & DeGregori, J. Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biol 8, e1000324 (2010).

4.         Wong, T.N. et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature (2014).

 

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