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

Carlota Arenillas; Lucía Celada; José Ruiz-Cantador; Bruna Calsina; Debayan Datta; Eduardo García-Galea; Roberta Fasani; Ana Belén Moreno-Cárdenas; Juan José Alba-Linares; Berta Miranda-Barrio; Ángel M Martínez-Montes; Cristina Alvarez-Escola; Beatriz Lecumberri; Ana González García; Shahida K Flores; Emmanuel Esquivel; Yanli Ding; Mirko Peitzsch; José-Ángel Robles-Guirado; Rita Maria Regojo Zapata; José Juan Pozo-Kreilinger; Carmela Iglesias; Trisha Dwight; Christopher A Muir; Amelia Oleaga; Maria Elvira Garrido-Lestache Rodríguez-Monte; Maria Jesús Del Cerro; Isaac Martínez-Bendayán; Enol Álvarez-González; Tamara Cubiella; Delmar Muniz Lourenço Jr; Maria Adelaide A Pereira; Nelly Burnichon; Alexandre Buffet; Craig Broberg; Paxton V Dickson; Mario F Fraga; José Luis Llorente Pendás; Joaquín Rueda Soriano; Francisco Buendía Fuentes; Sergio P A Toledo; Roderick Clifton-Bligh; Rodrigo Dienstmann; Josep Villanueva; Jaume Capdevila; Anne-Paule Gimenez-Roqueplo; Judith Favier; Paolo Nuciforo; William F Young Jr; Nicole Bechmann; Alexander R Opotowsky; Anand Vaidya; Irina Bancos; Donate Weghorn; Mercedes Robledo; Anna Casteràs; Laura Dos-Subirà; Igor Adameyko; María-Dolores Chiara; Patricia L M Dahia; Rodrigo A Toledo

doi:10.1158/2159-8290.CD-24-0943

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

Cancer Discov. 2025 May 2;15(5):1037-1062. doi: 10.1158/2159-8290.CD-24-0943.

Authors

Carlota Arenillas^{1

2

3}, Lucía Celada^{4

5}, José Ruiz-Cantador⁶, Bruna Calsina⁷, Debayan Datta¹, Eduardo García-Galea⁸, Roberta Fasani⁹, Ana Belén Moreno-Cárdenas¹, Juan José Alba-Linares^{4

5

10

11

12}, Berta Miranda-Barrio^{3

13

14

15}, Ángel M Martínez-Montes⁷, Cristina Alvarez-Escola¹⁶, Beatriz Lecumberri¹⁶, Ana González García⁶, Shahida K Flores¹⁷, Emmanuel Esquivel¹⁷, Yanli Ding¹⁸, Mirko Peitzsch¹⁹, José-Ángel Robles-Guirado²⁰, Rita Maria Regojo Zapata²¹, José Juan Pozo-Kreilinger²¹, Carmela Iglesias²², Trisha Dwight^{23

24}, Christopher A Muir^{25

26}, Amelia Oleaga²⁷, Maria Elvira Garrido-Lestache Rodríguez-Monte²⁸, Maria Jesús Del Cerro²⁸, Isaac Martínez-Bendayán²⁹, Enol Álvarez-González^{4

5

30}, Tamara Cubiella^{4

5}, Delmar Muniz Lourenço Jr³¹, Maria Adelaide A Pereira³¹, Nelly Burnichon^{32

33}, Alexandre Buffet^{32

33}, Craig Broberg³⁴, Paxton V Dickson³⁵, Mario F Fraga^{4

5

10

11

12}, José Luis Llorente Pendás^{2

4

36}, Joaquín Rueda Soriano^{14

37}, Francisco Buendía Fuentes^{14

37}, Sergio P A Toledo³⁸, Roderick Clifton-Bligh³⁹, Rodrigo Dienstmann^{8

40}, Josep Villanueva²⁰, Jaume Capdevila^{41

42}, Anne-Paule Gimenez-Roqueplo^{32

33}, Judith Favier³³, Paolo Nuciforo⁹, William F Young Jr⁴³, Nicole Bechmann¹⁹, Alexander R Opotowsky^{44

45}, Anand Vaidya⁴⁶, Irina Bancos⁴³, Donate Weghorn⁴⁷, Mercedes Robledo^{7

12}, Anna Casteràs^{3

48}, Laura Dos-Subirà^{13

14

15}, Igor Adameyko^{49

50}, María-Dolores Chiara^{4

5}, Patricia L M Dahia¹⁷, Rodrigo A Toledo^{1

2}

Affiliations

¹ Biomarkers and Clonal Dynamics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
² Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
³ Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
⁴ Health Research Institute of Asturias (ISPA), University of Oviedo, Oviedo, Spain.
⁵ Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain.
⁶ Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitario La Paz, Madrid, Spain.
⁷ Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁸ Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁹ Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
¹⁰ Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), University of Oviedo, Oviedo, Spain.
¹¹ Department of Organisms and Systems Biology (B.O.S.), University of Oviedo, Oviedo, Spain.
¹² Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
¹³ Integrated Adult Congenital Heart Disease Unit, Department of Cardiology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
¹⁴ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
¹⁵ European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, the Netherlands.
¹⁶ Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid, Spain.
¹⁷ Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center, San Antonio, Texas.
¹⁸ Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
¹⁹ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²⁰ Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
²¹ Department of Pathology, Hospital Universitario La Paz, Madrid, Spain.
²² Department of Pathology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
²³ Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, Australia.
²⁴ The University of Sydney, Sydney, Australia.
²⁵ Department of Endocrinology, St. Vincent's Hospital, Sydney, Australia.
²⁶ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
²⁷ Department of Endocrinology and Nutrition, Hospital Universitario de Basurto, Bilbao, Spain.
²⁸ Department of Pediatric Cardiology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
²⁹ Department of Pediatric Cardiology, Instituto de Investigación Biomédica (Cardiopatía Estructural y Congénita) and Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
³⁰ Department of Functional Biology, Genetic Area, University of Oviedo, Oviedo, Spain.
³¹ Endocrinology Division, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil.
³² AP-HP, Hôpital Européen Georges Pompidou, Département de Médecine Génomique des Tumeurs et des Cancers, Paris, France.
³³ Inserm, Centre de recherche des Cordeliers, Université Paris-Cité, Sorbonne Université, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
³⁴ Adult Congenital Heart Program, Division of Cardiology, Oregon Health and Science University, Portland, Oregon.
³⁵ Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee.
³⁶ Hospital Universitario Central de Asturias, Oviedo, Spain.
³⁷ Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
³⁸ School of Medicine, University of São Paulo, São Paulo, Brazil.
³⁹ Department of Endocrinology and Cancer Genetics Unit, Kolling Institute, Royal North Shore Hospital, Sydney, Australia.
⁴⁰ University of Vic - Central University of Catalonia, Vic, Spain.
⁴¹ Neuroendocrine and Endocrine Tumor Translational Research Program (NET-VHIO), Vall Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴² Department of Medical Oncology, Gastrointestinal and Endocrine Tumor Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Hospital Campus, Barcelona, Spain.
⁴³ Division of Endocrinology, Mayo Clinic, Rochester, Minnesota.
⁴⁴ Cincinnati Adult Congenital Heart Disease Program, Heart Institute, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio.
⁴⁵ Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
⁴⁶ Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
⁴⁷ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁴⁸ Department of Endocrinology and Nutrition, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴⁹ Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
⁵⁰ Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden.

Abstract

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. See related commentary by Lee, p. 875.

MeSH terms

Adaptation, Physiological* / genetics
Altitude*
Humans
Hypoxia* / genetics
Neoplasms* / genetics
Neoplasms* / pathology

Abstract

MeSH terms

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