Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes

Abstract

Genetic; Human tumors; Systemic hypoxia

Genètica; Tumors humans; Hipòxia sistèmica

Genética; Tumores humanos; Hipoxia sistémica

This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets.

The authors would like to thank especially patients and their families for their participation and contribution to this research study. We acknowledge IdiPAZ Biobank for the assistance in some tumor samples collection; VHIO’s Oncology Data Science (ODysSey) for carrying out some statistical analyses; European Network for the Study of Adrenal Tumors (ENS@T) and COST Action CA20122 Harmonisation for supportive networking; FERO Foundation for providing a startup grant for VHIO’s Biomarkers and Clonal Dynamics Laboratory led by R.A. Toledo; and Editage for its editing services. VHIO would like to acknowledge: the State Agency for Research (Agencia Estatal de Investigación) for the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033), the Cellex Foundation for providing research facilities and equipment, the CERCA Programme from the Generalitat de Catalunya for their support on this research, and the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation for supporting the Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI-I and CAIMI-II, grant no. 53/2021). In memory of Dr. José María Oliver, who played a pivotal role in the development of the field of Adult Congenital Heart Diseases in Spain and his early assessment of CCHD and PPGL association. The sponsors of this study listed below supported the costs related to the research experiments and salary of the investigators. Paradifference Foundation supported this PPGL research and provided funding support to J. Favier, M. Robledo, I. Adameyko, P.L.M. Dahia, and R.A. Toledo. The Pheipas Patient Association provided a research grant to R.A. Toledo for the study of PPGL tumors (grant #914300). C. Arenillas was supported by a CIBERONC predoctoral fellowship. R.A. Toledo holds a Miguel Servet-I research contract and a Plan Nacional grant by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy and Competitiveness from the Spanish government (grants #CP17/00199 and #PID2021-126297OA-I00). P.L.M. Dahia received grants from the NIH/NIGMS (#GM114102), NIH/NCI (#CA264248), Neuroendocrine Tumor Research Foundation (NETRF), VHL Alliance, Paradifference Foundation and is the holder of the Robert Tucker Hayes Distinguished Chair in Oncology. M.-D. Chiara received grants from the Institute of Health Carlos III (ISCIII) of the Ministry of Economy and Competitiveness from the Spanish government (grants #PI20/01754 and #PID2023-151388OB-I00). J. Capdevila was partially supported by the Institute of Health Carlos III (ISCIII; #PI20/00895) and co-funded by the European Union (ERDF/ESF)—A way to build Europe and the Enric Masip Foundation. C. Arenillas, B. Calsina, T. Cubiella, J. Favier, M. Robledo, M.-D. Chiara, and R.A. Toledo were awarded with travel grants by European Cooperation in Science and Technology (COST) Action CA20122 Harmonisation.