Patterns and mechanisms of structural variations in human cancer

Abstract

Next-generation sequencing technology has enabled the comprehensive detection of genomic alterations in human somatic cells, including point mutations, chromosomal rearrangements, and structural variations (SVs). Using sophisticated bioinformatics algorithms, unbiased catalogs of SVs are emerging from thousands of human cancer genomes for the first time. Via careful examination of SV breakpoints at single-nucleotide resolution as well as local DNA copy number changes, diverse patterns of genomic rearrangements are being revealed. These "SV signatures" provide deep insight into the mutational processes that have shaped genome changes in human somatic cells. This review summarizes the characteristics of recently identified complex SVs, including chromothripsis, chromoplexy, microhomology-mediated breakage-induced replication (MMBIR), and others, to provide a holistic snapshot of the current knowledge on genomic rearrangements in somatic cells.

Fig. 1

The history of structural variation research

Fig. 2. Types of basic genomic variations.

a Small mutations, base substitution and indels. b Simple structural variations, deletion, amplification, inversion, and interchromosomal translocation

Fig. 3. Patterns and proposed mechanisms of structural variations.

a Chromothripsis, showing a shattering and subsequent repair process. Telomere crisis and/or micronuclei by chromosome mis-segregation may induce chromothripsis. b Chromoplexy, showing a “closed chain” (upper) in the Circos plot. This is a multi-chromosomal translocation (lower). c MMBIR by template switching of the replication machineries. d BFB cycle, showing subtelomeric copy number increases and fold-back inversions. Proposed mechanisms are shown below. e Different patterns of SVs in BRCA1- and BRCA2-mutant breast cancers. f Patterns and formation of DMs and neochromosomes. DNA fragments can self-ligate, forming a ring structure, and are amplified (DMs). Fragments capturing centromeres and telomeres become neochromosomes. g Patterns and processes of L1 retrotransposition in the cancer genome. h HPV integration and regional rolling-circle amplification