A growing number of studies have applied evolutionary and ecological principles to understanding cancer. However, few such studies have examined whether phenotypic plasticity--the ability of a single individual or genome to respond differently to different environmental circumstances--can impact the origin and spread of cancer. Here, we propose the adaptive horizontal transmission hypothesis to explain how flexible decision-making by selfish genetic elements can cause them to spread from the genome of their original host into the genomes of other hosts through the evolution of transmissible cancers. Specifically, we hypothesize that such cancers appear when the likelihood of successful vertical transmission is sufficiently low relative to the likelihood of successful horizontal transmission. We develop an evolutionary optimization model of this hypothesis, highlight empirical findings that support it, and offer suggestions for future research. Generally, phenotypically plastic selfish genetic elements might play an important role in the evolution of transmissible cancers.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

Mutational processes in tumors create distinctive patterns of mutations, composed of neutral "passenger" mutations and oncogenic drivers that have quantifiable effects on the proliferation and survival of cancer cell lineages. Increases in proliferation and survival are mediated by natural selection, which can be quantified by comparing the frequency at which we detect substitutions to the frequency at which we expect to detect substitutions assuming neutrality. Most of the variants detectable with whole-exome sequencing in tumors are neutral or nearly neutral in effect, and thus the processes generating the majority of mutations may not be the primary sources of the tumorigenic mutations. Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches-revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies.

The genetic variation of our species reflects human demographic history and adaptation to diverse local environments. Part of this genetic variation affects individual responses to exogenous substances, such as food, pollutants and drugs, and plays an important role in drug efficacy and safety. This review provides a synthesis of the evolution of loci implicated in human pharmacological response and metabolism, interpreted within the theoretical framework of population genetics and molecular evolution. In particular, I review and discuss key evolutionary aspects of different pharmacogenes in humans and other species, such as the relationship between the type of substrates and rate of evolution; the selective pressure exerted by landscape variables or dietary habits; expected and observed patterns of rare genetic variation. Finally, I discuss how this knowledge can be translated directly or after the implementation of specific studies, into practical guidelines.