HIF Pathway Mutations found in Tibetan Highlander Populations leads to Increased Cancer Risk: REVIEW
DOI:
https://doi.org/10.58445/rars.4141Keywords:
HIF, HIF1a, Hypoxia, Tibetan Population, Cancer, Lung Cancer, NSCLC, PHD2Abstract
In the Tibetan population, Non-Small Cell Lung Cancer (NSCLC) was reported to be the sixth deadliest cancer (X. Wang et al., 2020). Mutations in the EGLN1 gene are present in 80% of people in Tibetan highlander populations. The EGLN1 mutations D4E and C127S are known to confer a 2x risk of developing lung cancer in this population. The PDH2 enzyme, coded for by the EGLN1 gene is a crucial part of hypoxia sensing in the Hypoxia-Inducible-Factor pathway (HIF). Under normal conditions, the HIF pathway is among the primary pathways responsible for homeostatic processes like increasing vascularization and proliferation of red blood cells (Graham & McCracken, 2019; Lukashev & Sitkovsky, 2008; Marxsen et al., 2004; Masoud & Li, 2015; van Vliet et al., 2021). Under hypoxic conditions, hydroxylase activity of PHD2 is suppressed, resulting in accumulation of HIF1α proteins that activate downstream target genes, inducing physiological changes especially in red blood cell production and increased vascularization. The result of these mutations in hypoxia is decreased degradation of the HIF1α subunits (Andersen et al., 2011; Delamare et al., 2023; Lanikova et al., 2017a; Lorenzo et al., 2014). This acts to enhance oxygen delivery under hypoxic conditions. It is hypothesized that under normoxic conditions, PDH2MUT induces HIF1 protein accumulation that promotes angiogenesis which may contribute to cancer growth and persistence. In terms of a NSCLC therapy, this Tibetan population expressing PDH2MUT would respond most preferably to HIF1α targeted therapy, as hypoxia in tumors leads to resistance to most other cancer therapies like radiotherapy and chemotherapy. The anti-VEGF monoclonal antibody bevacizumab (Avastin), has been expanded to the treatment of NSCLC. I will look at current and upcoming therapies to identify if the EGLN1 mutation associated with lung cancer can be treated with current technology and if the mutations would confer positive or negative response.
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