• Results of a VHIO led study show that up to 90% of chronically hypoxic patients have an EPAS1 alteration in their tumour, a gene critical for adapting to lack of oxygen in populations living at high-altitude such as Tibetans and Sherpas.
• EPAS1-driven adaptation mechanisms enable tumour cells to proliferate under hypoxia and similarly, allow high-altitude dwellers to survive low-oxygen conditions.
• Convergent evolution is a central concept in evolutionary biology, showing how different organisms can develop convergent traits independently when facing similar environmental challenges, in this instance hypoxia.
• Published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR), findings from this study suggest that achieving a deeper understanding of the links between natural adaptation and tumorigenesis could enhance cancer driver discovery and pave the way for identifying novel therapeutic targets.

Results of study directed by Rodrigo Toledo, Head of the Vall d’Hebron Institute of Oncology’s (VHIO) Biomarkers and Clonal Dynamics Group, show convergent genetic adaptation under hypoxia (lack of oxygen) between populations living at high-altitude in the Himalayan region such as Tibetans and Sherpas, and the development of oxygen-starved cancer cells.

Patients with cyanotic congenital heart disease (CCHD) are chronically hypoxic and have an estimated six-fold higher risk of developing pheochromocytoma and paraganglioma (PPGL) which is associated with neuroendocrine tumours (NETs) of the adrenal glands and/or paraganglia, respectively.

These cancers can continue to grow and proliferate under chronic hypoxia.

“With this study, we aimed to achieve deeper insights into how tumours can survive, grow, and even metastasize under low oxygen conditions, known as hypoxia. Our findings reveal a broad convergence in genetic adaptation in tumours that continue to develop and grow under hypoxia, and in high-altitude populations who thrive in such a challenging environment,” said Rodrigo Toledo, corresponding author of this present article.

A shared gene for survival

Sherpas have a unique variant of the EPAS1 gene, which is critical for hypoxia adaptation in high-altitude environments, such as the summit of Mount Everest.

Toledo’s team analysed the genomic profile of PPGL tumour samples from chronically hypoxic patients with CCHD and discovered that, among the 20,000 protein-coding genes of the human genome, the EPAS1 gene—found altered in Sherpas—was mutated with a frequency of up to 90% in these hypoxic cancer cells.

“It was fascinating to observe how these tumours, which can proliferate and even metastasize under a lack of oxygen, used exactly the same gene that enables Sherpas to adapt to hypoxia,” added Rodrigo Toledo.

Convergent evolution: nature’s shared adaptations

Convergent evolution is a process where unrelated species independently develop similar traits to overcome comparable environmental challenges.

For example, both whales and bats developed echolocation to move around in pitch darkness.

Despite their evolutionary distance, these species share the use of the same gene (SLC26A5) to develop echolocation.

“Similarly, cancer genome projects have shown that different tumour types often share the same mutations in specific sets of genes, such as TP53, KRAS and BRAF, among others, which boost their growth. This suggests that, in addition to natural populations, tumours also have degrees of genetic convergence,” observed Toledo.

“The most innovative aspect of this study is our discovery that when natural populations and tumours face similar environmental stresses such as lack of oxygen, they both depend on the same gene to survive. This level of convergence shows that nature shares successful solutions, whether it be in the Himalayan mountains or in the hypoxic tumour microenvironment," said Carlota Arenillas, a PhD Student of Toledo’s group and first author of the article.

These results could open new directions in using genetic adaptations of natural environments as a starting point to analyse datasets from cancer genomic studies and existing preclinical models toward identifying key genes for cancer survival and novel therapeutic targets.

“Our findings could help guide future studies exploring the links between natural adaptation and tumorigenesis, facilitating the identification of new cancer drivers and therapeutic vulnerabilities. As an example, we aim to identify the genes responsible for adaptation to regions with high levels of ultraviolet rays and analyse them in aggressive skin cancers such as melanoma," concluded Toledo.

This research has been possible thanks to the support received from the Paradifference Foundation, the PHEiPAS Patient Association, the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), and the European Network for the Study of Adrenal Tumours (ENSAT).

Rodrigo Toledo also has the support of the "la Caixa" Foundation through a CaixaImpulse grant, a Miguel Servet research contract, a grant from the National Plan of the Institute of Health Carlos III (ISCIII) of the Spanish Ministry of Economy and Competitiveness, a CaixaImpulse scholarship from the "la Caixa" Foundation and a start-up grant from the FERO Foundation.

Source: Vall d'Hebron Institute of Oncology