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Divergent mutational processes distinguish hypoxic and normoxic tumours.

ABSTRACT: Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

SUBMITTER: Bhandari V

PROVIDER: S-EPMC7002770 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Divergent mutational processes distinguish hypoxic and normoxic tumours.

Bhandari Vinayak V Li Constance H CH Bristow Robert G RG Boutros Paul C PC

Nature communications 20200205 1

Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, ...[more]

PMID: 32024819

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Project description:Platinum-based chemotherapy is the main treatment element to achieve cure for patients with metastatic germ cell tumours. Drug resistance in testicular germ cell tumours (TGCTs) is rare and the reasons are not fully understood. While recent investigations have indicated decreased efficacy of chemotherapy in several tumour types under hypoxic conditions, this aspect has not been investigated in TGCTs so far. Furthermore, for cisplatin - the most active drug in this disease - controversial effects of hypoxia on cytotoxic efficacy have been reported. The relative efficacy of cytotoxic agents for the treatment of TGCT patients was studied in three different cell lines derived from human embryonal carcinomas (EC) in an in vitro hypoxia model. NT2, 2102 EP, and NCCIT were tested for their sensitivity towards cisplatin, etoposide, bleomycin, 4-OOH-ifosfamide, carboplatin, paclitaxel, gemcitabine, oxaliplatin, irinotecan, and mitomycin C under normoxic and hypoxic conditions using the MTT assay. Inhibitory concentrations IC(50) of the tested agents under both conditions were compared. Selected results were confirmed by flow-cytometric assessment of the apoptotic index. In all cells, doubling times were prolonged in hypoxia (NT2<NCCIT<2102 EP). All drugs were less effective under hypoxic conditions, including mitomycin C (eg, 1.6-fold increase of IC(50) in hypoxia compared to normoxia for NT2) and cisplatin (eg, NT2: two-fold increase). The relative effect of hypoxia on the IC(50) depended mainly on the cell line, and to a lesser extent on the drug. The results indicate that the reduced cell proliferation in hypoxia might be an important factor, but not the only determinant of a reduced cytotoxicity. In view of the broad spectrum of drugs with different modes of action tested, the relative resistance cannot be mediated by substance-specific resistance mechanisms like hypoxia-induced upregulation of P-glycoprotein or increased DNA-repair capacity, since many unrelated drugs were affected to a comparable extent in their efficacy by hypoxia. This study also provides the rationale to test the hypothesis whether improving tumour oxygenation by raising haemoglobin concentrations, for example, with erythropoietin in patients with TGCTs receiving chemotherapy may improve the outcome.

Project description:Key pointsTheoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange.AbstractThe longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50 = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50 = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation ( Sa,O2 ) was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake ( V̇O2max ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in V̇O2max between trials was related to the change in SaO2 (r = -0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

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Divergent mutational processes distinguish hypoxic and normoxic tumours.

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Divergent mutational processes distinguish hypoxic and normoxic tumours.

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