A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs.
Genome rearrangements including gene amplification are frequent properties of tumor cells, but how they are related to the tumor microenvironment is unknown. Here, we report direct evidence for a causal relationship between hypoxia, induction of fragile sites, and gene amplification. Recently, we showed that breaks at fragile sites initiate intrachromosomal amplification. We demonstrate here that hypoxia is a potent fragile site inducer and that, like fragile sites inducing drugs, it drives fusion of double minutes (DMs) and their targeted reintegration into chromosomal fragile sites, generating homogeneously staining regions (HSRs). This pathway operates efficiently for DMs bearing different sequences, suggesting a model of hypoxia-driven formation of the HSRs containing nonsyntenic sequences frequently observed in solid tumors.
Coquelle
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Unité de Génétique Somatique, URA CNRS 1960, Institut Pasteur, Paris, France.
Toledo
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Stern
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Bieth
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Debatisse
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D019457:Chromosome Breakage / Q000235:genetics; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D006224:Cricetinae; D003412:Cricetulus; D018432:Drug Resistance, Multiple / Q000235:genetics; D005111:Extrachromosomal Inheritance; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1