The role of mitochondria in cancer incidence and survival: a new paradigm in gender oncology

Background Sex significantly influences the occurrence and outcomes of various cancers, yet it is often overlooked in cancer research. The incomplete understanding of sex disparities in cancer, attributed to behavioural, social, and environmental factors, underscores the necessity of considering sex-specific biological aspects. Variations in mitochondrial function, regulated by mitochondrial DNA (mtDNA) profiles and epigenetic modifications, play crucial roles, but the intricate interplay between nucleus and mitochondria remains inadequately explored. Mitochondria, influenced by sex hormones, impact cellular processes, potentially affecting cancer susceptibility by managing ROS and iron levels in response to internal and external risk factors. Hypothesis Our hypothesis suggests that mitochondrial metabolism is a fundamental mechanism driving sex-specific variations in the development and prognosis of cancer. Additionally, we posit that the epigenetic control of mtDNA, coupled with the interplay between mitochondrial and nuclear DNA, may offer insights into the sex differences observed in the individual response to risk factors and their resulting cancer susceptibility. Aims - Describe the differences in cancer diagnosis and survival by sex for all cancer sites i and investigate whether sex differences are mediated by lifestyle or environmental risk factors in Europe. - Investigate the impact ofr risk factors on mtDNA copy number (mDNA-CN) and methylation (mtDNAm), and nDNA methylation (nDNAm). - Shed light on the pathophysiological mechanism by which mitochondrial metabolism may influence the risk of tumour onset and survival by measuring oxidative stress biomarkers and iron homeostasis. - Assess the associations of mtDNA-CN, mtDNAm, and nDNAm interactions and cancer risk and survival. - Disentangle the role of sex in the epigenetic regulations of mitochondria in response to risk factors and their interactions with nuclear genes on carcinogenesis and cancer survival. Experimental Design We propose conducting a case-cohort study nested in the EPIC Italy study, involving 600 already diagnosed cancer cases and 600 randomly sampled sub-cohort participants. This study will focus on highly prevalent cancer, with a higher male-to-female ratio in incidence and survival and limited prior research attention (gastric, rectal, liver, pancreatic, kidney, and glioma tumours). We will perform DNAm analysis on nucleic and mitochondrial genomes, mitochondrial functionality assays, oxidative stress estimation and measurement, and iron status assay on the biological samples of the EPIC cohort cases and controls. Expected Results We will elucidate the underlying mechanisms driving the disparities in cancer occurrence and outcomes between sexes. Specifically, we will delve into the role of mDNA and the epigenetic crosstalk between mitochondrial and nuclear DNA. By leveraging advanced epidemiological methods, mathematical modelling, and artificial intelligence, we seek to provide a comprehensive understanding of the multifaceted mechanisms shaping sexual dimorphism in oncology. Embracing the concept of sex as a spectrum will enrich our comprehension, offering deeper insights into how sex differences impact cancer susceptibility and survival pathways. Impact On Cancer Shedding light on the risks associated with mtDNA modifications could offer vital perspectives into the mechanisms behind sex discrepancies in oncology, paving the way for ground-breaking strategies from preventive measures to personalized treatments. The alterations in mDNA hold promise as potential tumour markers and prognostic tools for individuals with malignant diseases.