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.

Hypoxia increases mutational load of breast cancer cells through frameshift mutations

“…However, a recent study suggested that large number of mutations were identified in patients with hypoxic tumors with higher incidence in deletions, duplications, and single nucleotide changes. 27 The authors also identified mutational signatures from single base substitutions and frameshift mutations correlating with defective DNA repair (homologous recombination and mismatch repair), suggestive of hypoxic contribution to such genotypes. 27 An increase in insertions and deletions was observed in comparison to single nucleotide variations.…”

“…27 The authors also identified mutational signatures from single base substitutions and frameshift mutations correlating with defective DNA repair (homologous recombination and mismatch repair), suggestive of hypoxic contribution to such genotypes. 27 An increase in insertions and deletions was observed in comparison to single nucleotide variations. Rospo and coworkers demonstrated that the incidence of insertions and deletions was much more prevalent in colorectal cancers having DNA repair defects like polymerase E mutations and high microsatellite instability.…”

Tumor Microenvironment Status Predicts the Efficacy of Postoperative Chemotherapy or Radiochemotherapy in Resected Gastric Cancer

“…Interestingly, active immune infiltration in fTME seemed to increase hypoxia level. Recently, elevated hypoxia was also found to be associated with increased TMB across cancer types including GC ( 40 ). Because high TMB promotes immune infiltration by producing more novel peptide epitopes or neoantigens ( 41 ), this finding indicated again the association between immune infiltration and hypoxia.…”

Analysis of the TCGA Dataset Reveals that Subsites of Laryngeal Squamous Cell Carcinoma Are Molecularly Distinct

“…The Supplemental Materials and the scores for intratumor hypoxia were downloaded from Bhandari et al and Buffa et. al, respectively [ 57 , 58 , 69 ]. Mann-Whitney U tests with FDR adjustment were used to compare intercohort scores [ 11 , 52 ].…”