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 proper ties of tumor cells, but how they are related to the tumor microenviro nment is unknown. Here, we report direct evidence for a causal relatio nship between hypoxia, induction of fragile sites, and gene amplificat ion. Recently, we showed that breaks at fragile sites initiate intrach romosomal amplification. We demonstrate here that hypoxia is a potent fragile site inducer and that, like fragile sites inducing drugs, it d rives fusion of double minutes (DMs) and their targeted reintegration into chromosomal fragile sites, generating homogeneously staining regi ons (HSRs). This pathway operates efficiently for DMs bearing differen t sequences, suggesting a model of hypoxia-driven formation of the HSR s containing nonsyntenic sequences frequently observed in solid tumors .