Molecular Detection of Oncogenic Gene Rearrangements

Key points

Introduction

The description of the first gene rearrangements goes back to the 1980s, ^1 , 2 approximately a decade after the discovery of chromosome banding. ³ Since then, advances in molecular technologies for the detection of oncogenic gene rearrangements have revolutionized the field of precision medicine in a range of different clinical settings, from assisting diagnosis to targeted therapy options for many tumor types. The functional consequence of gene rearrangements is production of a chimeric protein or deregulation of the involved genes. These consequences result from structural DNA changes, such as translocations, inversions, and even copy number alterations (eg, gene deletions) ( Fig. 1 ), as opposed to single nucleotide variants commonly referred to as mutations. In fact, it has been recently recommended that gene fusions should be described with a double colon (::) separator (eg, BCR :: ABL1 ) ⁴ akin to the International System for Human Cytogenetic Nomenclature chromosome break and reunion symbol highlighting the importance of structural alterations in their development. Therefore, the methods used in gene fusion detection are designed to capture these larger-scale changes, now to/at the nucleotide-level resolution via high-throughput sequencing technologies. Herein, the genomic tools identifying gene fusions are discussed from conventional low-resolution to high-throughput high-resolution methods ( Fig. 2 ). Albeit immunohistochemical detection of gene fusions at the protein level is beyond the scope of this review, it is worth noting that there are successful examples used in routine clinical practice, particularly in the setting of non–small cell lung carcinoma.