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A variety of mutational mechanisms shape the landscape of somatic mutations in cancer genomes. Although the contribution of single nucleotide mutations is well studied, getting a hold of structural genomic rearrangements is more difficult due to their complexity and diversity in sizes and classes. Here, we discuss the incidence of complex genomic rearrangements and their impact on cancer development and progression.Catastrophic genome rearrangements have recently been described in various cancer genomes. Such complex genomic rearrangements may be a result of local shattering of chromosomes followed by reassembly of DNA fragments, a process termed chromothripsis. In addition, DNA replication errors may lead to complex genomic rearrangements in cancer. Complex reshuffling of chromosomes can cause formation of gene fusions, disruption of tumor suppressors, and amplification of oncogenes. Furthermore, the occurrence of chromothripsis has been associated with poor prognosis in neuroblastoma, melanoma, and multiple myeloma.Complex genomic rearrangements, such as chromothripsis, may affect cancer gene function and thereby have a major impact on cancer progression, prognosis, and therapy response.