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The role of chromosomal rearrangements in tumorigenesis and cancer progression has received substantial attention in recent years.1–3 Chromosomal rearrangements were initially described in hematologic malignancies such as chronic myelogenous leukemia (CML)4,5 and Burkitt’s lymphoma,6 where they have been used both for diagnosis and to direct targeted therapies. Subsequently, recurrent translocations were also found in rare classes of soft tissue tumors such as Ewing’s sarcoma7,8 and synovial sarcoma.9Recurrent translocations were not initially identified in many of the common solid, epithelial tumors, in part, because of the limitations of standard cytogenetic analyses and the underlying biological diversity. However, with the emergence of new technologies that allow more comprehensive genomic analysis of solid cancers, genomic rearrangements have been identified in many solid tumors, including breast cancer. This has enabled the identification of subsets of common solid tumors that harbor novel fusions or rearrangements that were not previously appreciated, eg, ALK fusions in non-small cell lung cancer (NSCLC), and has provided novel therapeutic approaches.

Tumor genomic profiling encompasses a variety of sequencing techniques that use next-generation sequencing methods, eg, DNA and RNA sequencing (RNA-seq). Genomically-guided therapy or targeted therapy refers to the selection of a treatment strategy based on the results of tumor genomic profiling, where a clinical response is more likely to occur in the presence of the relevant genomic target. Association between the presence of a genomic alteration and drug response defines a genomic alteration as a predictive biomarker. Such biomarkers have been critical to personalizing the approach to cancer treatment and improving patient outcomes. In contrast, prognostic biomarkers define disease trajectory in the untreated individual. Although some biomarkers can be both predictive and prognostic, biomarkers that are only prognostic can be useful in defining subsets of patients at risk for poor outcomes. Such knowledge allows the treating physicians to determine whether more aggressive or alternative approaches should be undertaken for those patients. Many genomic alterations, including point mutations, deletions/insertions, amplifications, and rearrangements, serve as predictive biomarkers, prognostic biomarkers, or both.

Genomic rearrangements refer to structural changes in the genome that are caused by breakage of DNA followed by erroneous rejoining and replication. These include events that alter copy number, such as deletion, tandem duplication, and amplification, as well as others that maintain copy number, such as reciprocal translocations and inversions (Figure 1A–C). Rearrangements encompass gross alterations of the whole chromosome or part of a chromosome and do not include the more commonly studied single base mutations or small deletions and insertions of a few base pairs in length. A special class of rearrangements known as interchomosomal or intrachromosomal rearrangements is the result of interactions between distant regions of the genome or even within the same chromosome, respectively. This type of rearrangement can lead to fusion of two disrupted genes, resulting in an altered transcript and a fusion protein (Figure 1B). These fusions can potentially activate, reduce, or eliminate the original function of the gene product(s) or generate a chimeric protein. Neomorphic functions may also result and have been described, eg, gain of function TP53 mutations and specific PIK3R1, MYOD1, and IDH1 mutations, and are implicated as driver mutations in cancer.10–13

(To view a larger version of Figure 1, click here.)