Capdevila, Jaume

Abstract 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. See related commentary by Lee, p. 875

e16205 Background: Data about neuroendocrine neoplasms (NENs) patients with SARS-CoV-2 are scanty and specific indications for clinical practice are missing. Our aim is to create an international registry about NENs patients affected by SARS-CoV-2 positivity to give a worldwide representation of the situation. Methods: This is an observational retrospective/prospective multicenter survey based on a direct email invitation. All types of NEN are eligible except SCLC and MiNEN. Patients fulfilling the inclusion criteria from March 1st, 2020 up to the end pf pandemic will be recruited. Electronic CRFs are filled out using the REDCap database. Local Institutional Review Board approval is required before data entry. Results: Eighty-one centers, 24 in and 57 outside Italy, representing 39 countries and 5 continents, were contacted. Fourteen centers did not respond and 15 declined the invitation. Among the remaining 52, 6 centers are currently recruiting and 8 are active but not recruiting yet. As of the current abstract submission deadline, 67 patients have been included, mostly GEP-NET (75%), non-functioning (86%), metastatic (85%) and on active treatment [47% somatostatin analogs (SSAs), 10% everolimus, 12% tirosin-kinase inhibitors (TKIs), 10% peptide receptor radionuclide therapy (PRRT), 15% chemotherapy]. Median age at NEN diagnosis was 57 years whilst the median age at SARS-CoV-2 diagnosis was 62 years. Almost all patients reported COVID-19-related symptoms, more commonly fever (67% of patients), cough (55%) and dyspnea (51%), in 28% of cases exertional and in 22% at rest. More than one third of patients (n, 24) had a pneumonia. The most common therapies for COVID-19 were antibiotics, steroids and hydroxychloroquine. Eleven patients (16%) needed oxygen therapy, three (4%) sub-intensive care and none intensive care. Fifty-six patients (84%) clinically recovered, six (9%) with sequelae, whereas five (7%) died. Among these latter 4 had a NET and 1 a NEC, and no patients have been receiving chemotherapy. With regard to the anti-tumor therapy no change occurred in 66% of patients, temporary interruption in 30%, and definitive discontinuation in 3%, 2% missing. Conclusions: Most of the NEN patients completely recovered from COVID-19, in many cases without any anti-tumor therapy adjustment. No clear correlations were observed with type, primary site and treatment of NEN. The recruitment is ongoing.