Divergent mutational processes distinguish hypoxic and normoxic tumours

Area of Science:

• Genomic Medicine
• Cancer Biology
• Tumor Microenvironment

Background:

• Tumor hypoxia is prevalent in primary cancers and associated with therapeutic resistance.
• The pan-cancer molecular characteristics of tumor hypoxia, including its relationship with mutational processes and evolutionary features, are not well understood.
• Understanding hypoxia's role is crucial for improving cancer treatment strategies.

Purpose of the Study:

• To investigate the pan-cancer molecular hallmarks of tumor hypoxia.
• To explore associations between hypoxia and mutational processes, non-coding driver genes, and cancer evolution.
• To quantify hypoxia across diverse cancer types using whole genome sequencing data.

Main Methods:

• Analysis of whole genome sequencing data from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium.
• Quantification of hypoxia in 1188 tumors across 27 cancer types.
• Statistical analysis of associations between hypoxia levels, mutational load, mutational signatures, and driver gene mutations.

Main Results:

• Elevated hypoxia correlates with increased mutational load across various cancer types, independent of mutational class.
• The proportion of mutations linked to unknown etiological mutational signatures is directly associated with hypoxia levels.
• Driver mutations in TP53, MYC, and PTEN are enriched in hypoxic tumors, with PTEN mutations interacting with hypoxia to influence tumor evolution.

Conclusions:

• Hypoxia significantly shapes the genomic and evolutionary landscapes of cancer.
• Hypoxia is associated with specific mutational processes and driver gene alterations.
• Further research into hypoxia's role may lead to novel therapeutic approaches for cancer.