1.5.12 Structural Variant Definition

Structural Variant Definition is the description of a broad category of genetic alteration involving relatively large-scale rearrangements of a cell's DNA, in which segments of the genome are moved, reoriented, duplicated, or joined together in configurations that differ substantially from the normal arrangement, distinguishing structural variants from smaller sequence-level changes such as single nucleotide variants. Structural variants typically involve stretches of DNA large enough to encompass entire genes or multiple genes, making them a particularly consequential form of genetic change in cancer.

Categories of Structural Variant

Duplications

A duplication involves the copying of a segment of DNA so that an additional copy is inserted elsewhere within the genome, increasing the overall representation of the genes contained within that segment, closely related to the broader concept of copy number gain.

Inversions

An inversion occurs when a segment of DNA is reversed in orientation within the genome, remaining in its original location but flipped relative to its normal direction, which can disrupt the function of genes located within or at the boundaries of the inverted segment.

Translocations

A translocation involves the relocation of a segment of DNA from one position in the genome to a different, often distant, position, sometimes joining together genetic material from two normally separate regions and occasionally fusing parts of two different genes into a single abnormal combination.

Functional Consequences of Structural Variants

Disruption of Gene Structure

A structural variant occurring within or across the boundaries of a gene can directly disrupt that gene's normal structure, potentially eliminating its function or altering it in unpredictable ways depending on precisely how the rearrangement interrupts the gene's sequence.

Formation of Fusion Genes

A translocation that joins portions of two separate genes together can create a novel fusion gene, producing an abnormal combined product that may display new or inappropriately regulated activity not present in either of the original, unaltered genes.

Altered Gene Regulation

Structural variants can also reposition a gene relative to regulatory elements that control its activity, causing that gene to be expressed at inappropriate levels or under inappropriate conditions even if the gene's own sequence remains largely intact.

Structural Variants as Drivers or Passengers

Potential for Substantial Functional Impact

Because structural variants often affect large segments of the genome and can disrupt or recombine entire genes, they carry substantial potential to function as significant driver alterations when they affect genes relevant to cancer development.

Contribution to Overall Genomic Instability

The accumulation of structural variants within a cancer genome often reflects a broader underlying state of genomic instability, contributing both to the generation of potential driver alterations and to the larger set of incidental passenger changes present within a tumor.

Relevance to Cancer Cell Biology

Structural variants represent a distinctive and often highly consequential category of genetic alteration in cancer, capable of disrupting gene function, creating novel fusion genes, and altering gene regulation through large-scale genomic rearrangement, providing an essential complement to smaller-scale sequence and copy number alterations in fully characterizing the genetic changes that drive malignant transformation.