Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes

Abstract

AbstractEPAS1HIF2αis the primary gene implicated in systemic hypoxia adaptation. Conversely, aberrantly activatedEPAS1HIF2αacts 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,EPAS1HIF2αgenetic variants were positively selected within sympathetic tumors developed under hypoxia, with a consistently high frequency of 90%. Bulk and single-cell RNA sequencing followed byin vitrostudies have shown that hypoxia andEPAS1HIF2αgain-of-function tumor mutations induceCOX4i2expression 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 theEPAS1HIF2αgenetic 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.