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EPAS1HIF2a is the primary gene implicated in systemic hypoxia adaptation. Conversely, aberrantly activated EPAS1HIF2a acts as a tumor driver against which anti-tumor therapeutics are proven effective. We elucidated connections between adaptation to systemic hypoxia in high-altitude populations, such as Tibetans and Sherpas, and human tumors. Similar to the accelerated adaptability observed in high-altitude populations via genetic introgression, tumors from patients with hypoxia since birth exhibited impaired DNA repair and increased mutation burden. As in high-altitude dwellers, EPAS1HIF2a genetic variants were positively selected within sympathetic tumors developed under hypoxia, with a consistently high frequency of 90%. Bulk and single-cell RNA sequencing followed by in vitro studies have shown that hypoxia and EPAS1HIF2a gain-of-function tumor mutations induce COX4i2 expression and impair mitochondrial respiration, indicating that decreased cellular oxygen consumption may confer a proliferative advantage in hypoxia. Analyzing medical data from a patient cohort with hypoxia since birth who developed/did not develop tumors revealed tissue-specific and time-dependent tumorigenic effects of systemic hypoxia, which is limited to oxygen-sensitive and responsive cells, particularly during the postnatal period. This study supports connections between the EPAS1HIF2a genetic adaptation in human tumors developed under systemic hypoxia to populations living in high altitudes. The genetic adaptations in populations to different stressors can be explored further to understand tumorigenesis and tumor evolution.