Cancer initiation is influenced by sex-biased tissue environment or imbalanced hormones

Gender difference has long been observed in non-reproductive cancer susceptibility and prognosis. In addition to external factors, biological sex bias, such as sex chromosomes, hormones, and immune function, is thought to influence the evolutionary process of cancer initiation as a selective pressure. However, the extent and mechanism of how sex bias influences cancer initiation remains largely unknown. In this study, we show that tissue sex bias directed by gonadotropin-releasing hormone varies among different tissues and is associated with two distinct age-specific cancer incidence patterns: the parallel and nonparallel patterns. In addition, imbalances in estrogen and thyroid hormone are shown to correlate with levels of hypoxia induce factors, resulting in three phases (hypoxia, hyperoxia, and “chaotic-oxia”) that exist across the majority of TCGA cancers and are linked to certain cancer subtypes, including cancers with microsatellites, CpG island methylator phenotype or hypermethylation. Our results suggest that sex-biased tissue environments and imbalanced hormones could influence the evolutionary process of cancer initiation, emphasizing the importance of maintaining hormone homeostasis for cancer prevention and providing insights for improving therapy for cancer types with hormone imbalances. ### Competing Interest Statement The authors have declared no competing interest.