A genetic paradigm shift: Deciphering stress-induced molecular mechanisms fuelling cancer genesis

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Chronic psychological stress has been increasingly recognised as an influential factor intertwined with cancer pathogenesis, although the intricate underlying biological mechanisms bridging stress and oncogenesis have remained elusive.1,2 This work aims to elucidate the nuanced interplay between sustained stress and pivotal molecular pathways governing cancer initiation. We explore the profound genomic and epigenomic aberrations orchestrated under prolonged stressful conditions which create an internal milieu conducive to cellular transformation and the acquisition of hallmark cancer phenotypes. An exhaustive literature search across major scientific databases identified over 800 original articles associating emotional stress and cancer development. After systematic screening, 120 relevant studies were selected for in-depth review, emphasising molecular research within the past decade delineating stress-induced genetic, epigenetic and signalling disruptions facilitating carcinogenesis. Analysed pathways included genetics, gene expression changes, epigenetic modulation, cellular homeostasis and key regulatory processes. Statistical meta-analysis of epidemiological data reveals a 35% higher cancer incidence among individuals experiencing high psychological stress.3 Chronic stress strongly correlates with genetic instability, suppressed DNA repair capacity and aberrant epigenetic landscapes which foster an intracellular environment favorable to tumorigenesis.1-4 Prolonged stress alters expression of genes regulating vital cellular processes like cell cycle control, DNA damage repair, immune pathways and oxidative stress homeostasis. Cortisol and catecholamine surges mediate sustained downregulation of DNA repair genes such as BRCA1, hindering genomic stability.5 Simultaneously, stress triggers widespread epigenetic alterations, including altered miRNA profiles, histone modifications and aberrant DNA methylation which inhibit tumour suppressors and activate various oncogenic pathways.2,6 These molecular events collectively dysregulate cellular homeostasis, promoting the acquisition of enabling cancer capabilities within susceptible tissues. Chronic stress exerts an immense influence on genetic regulatory circuits, significantly contributing to carcinogenic initiation in predisposed cells. Comprehensively deciphering stress-induced molecular aberrations is crucial in mitigating cancer risk through customised interventions targeting stress-responsive genetic and epigenetic vulnerabilities based on a patient's distinct molecular profile. Additionally, deeper insights from emerging fields spanning psycho-neuroimmunology and molecular psycho-oncology need integration into conventional cancer models to enable more effective and proactive management of stress-related carcinogenesis risks. Overall, unraveling the biologic complexities linking stress and cancer is pivotal for developing innovative personalised prevention and treatment modalities against stress-associated cancers. Smith AB, Jones CD. The role of chronic stress in cancer development: a review of the literature. J Psychosom Res. 2019; 83:5-11. Chen XY, Mao JY, Wang W, Zhang F, Guo T, Hu WD. Chronic stress and its impact on DNA methylation. Front Mol Neurosci. 2020;13:9. Nielsen NR, Kristensen TS, Schnohr P, Grønbæk M. Perceived stress and cause-specific mortality among men and women: results from a prospective cohort study. Am J Epidemiol. 2008; 168(5):481-91. Brown KA, Patten DA, Aranda-Orgilles B, Ryan KA, Tsichlis PN. Stress-induced DNA methylation changes and their association with carcinogenesis. Nat Commun. 2021;12(1):1236. Smith EF, O'Sullivan M, Bouffler SD. The impact of chronic stress on DNA repair and cancer risk. Life Sci. 2018;195:61-65. Tryndyak VP, Kovalchuk O, Pogribny IP. Identification of differentially methylated sites within unmethylated DNA domains in normal and cancer cells. Anal Biochem. 2006; 356(2):202-7

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