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Tumor Hypoxia Associated With Cancer Driver Mutation Signatures in 19 Tumor Types

NEW YORK (GenomeWeb) – An international team of researchers has mapped the landscape of tumor hypoxia in 19 tumor types in order to determine what effect such low levels of molecular oxygen can have on the tumors' mutational signatures.

The tumor microenvironment is peppered with subregions of hypoxia in approximately half of all solid tumors, and these regions can vary in their size and extent, the researchers noted in a study published today in Nature Genetics. Tumor hypoxia is associated with poor clinical prognosis and elevated genomic instability, resistance to chemotherapy and radiotherapy, immune dampening, development of tumor stem cell-protective niches, and increased proclivity for distant metastasis.

The researchers quantified hypoxia in 8,006 tumors across 19 tumor types in The Cancer Genome Atlas (TCGA) and the Canadian Prostate Cancer Genome Network (CPC-GENE) by using mRNA-based hypoxiasignatures and found that it was associated with elevated genomic instability in 10 of the tumor types. They also noted that hypoxic tumors in all 19 tumor types exhibited characteristic driver-mutation signatures.

Overall, they found that squamous cell tumors of the head and neck, cervix, and lung were the most hypoxic, whereas adenocarcinomas of the thyroid and prostate were the least hypoxic.

When they focused on localized prostate cancer — for which they had whole-genome-sequencing data linked to direct intratumoral oxygen measurements — the investigators found that hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN, and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing features resembling tumor nimbosus, which is an aggressive cellular phenotype.

They also found that tumor hypoxia was associated with unique microRNA abundance profiles, with 84 percent of measured miRNAs showing correlations with tumor hypoxia. "We confirmed that the abundance of miR-133a-3p was significantly associated with hypoxia in the CPC-GENE cohort and a third independent cohort with 97 subjects," the authors wrote. "The abundance of miR-133a-3p is associated with that of several proteins, including the tumor suppressor BIN1 and the phosphotransferase PGM5."

Overall, the team concluded, there is extensive intertumor- and intratumor-type heterogeneity in tumor hypoxia, which suggests that subsets of patients with a range of solid tumors with genetic instability may benefit from hypoxia-targeting therapy. The investigators suggested, therefore, that clinical trials of hypoxia-targeting agents should focus on solid tumors with both elevated hypoxia and associated genetic instability.

"The metabolic reprogramming of cells via hypoxia can now be associated with a series of distinct genomic alterations. Some molecular aberrations show intertumor-type variations in their associations with hypoxia, whereas others, such as SNVs and CNAs in TP53, show a strong consistency as a pan-cancer correlate of hypoxic tumors," they wrote. "TP53 mutations are enriched in hypoxic tumors within each breast cancer subtype, thus supporting the idea that they are a genomic consequence of tumor hypoxia. This highlights the need to further examine the somatic-mutational architecture of other cancer types, such as pediatric tumors, in relation to hypoxia in large, well-powered data sets."