Manifestation, mechanisms and mysteries of gene amplifications

Gene amplifications are essential features of advanced cancers and have prognostic as well as therapeutic significance in clinical cancer treatment. Models explaining the amplification process, such as breakage–fusion–bridge cycle and excision and unequal segregation of extrachromosomal DNA fragments, predict that independent DNA double-stranded breaks must occur to induce amplification formation. Many cellular, tissue and environmental factors induce DNA damage and amplifications. Also labile DNA sequence features like fragile sites facilitate amplifications. Although, databases and data mining tools of various genomic attributes are already available, extra-large scale systems biology endeavors to decipher dynamics, interactions and dependencies between different factors contributing to amplification process fail, because current databases of DNA copy number aberrations and fragile sites comprise conventional cytogenetics results obtained at far too coarse chromosome band resolution. Array comparative genomic hybridization (aCGH) enables genome-wide gene copy number measurements and amplification detection at molecular genetic resolution. Similarly, cloning and sequencing of fragile sites produce mapping information of vastly improved resolution. In conclusion, databases of aCGH and sequenced fragile sites are needed to resolve the mechanisms of gene amplifications in systems biology configuration.