Chromosome structural variation in tumorigenesis: mechanisms of formation and carcinogenesis

Abstract

With the rapid development of next-generation sequencing technology, chromosome structural variation has gradually gained increased clinical significance in tumorigenesis. However, the molecular mechanism(s) underlying this structural variation remain poorly understood. A search of the literature shows that a three-dimensional chromatin state plays a vital role in inducing structural variation and in the gene expression profiles in tumorigenesis. Structural variants may result in changes in copy number or deletions of coding sequences, as well as the perturbation of structural chromatin features, especially topological domains, and disruption of interactions between genes and their regulatory elements. This review focuses recent work aiming at elucidating how structural variations develop and misregulate oncogenes and tumor suppressors, to provide general insights into tumor formation mechanisms and to provide potential targets for future anticancer therapies.

Keywords: Cancer; Chromothripsis; Structural variation; Translocation.

Fig. 1

Proposed mechanisms involved in the formation of structural variation. a DSBs can be repaired by HR, NAHR, NHEJ, MMEJ, and SSA. b FoSTeS and MMBIR model. During DNA replication, the DNA replication fork can stall, leaving the lagging strand to invade another replication fork using complementary template microhomology to anneal and extend by DNA synthesis. The failure to repair by BIR can induce MMBIR, which drives the strand invasion of non-sister templates using microhomology-containing regions, thereby giving rise to chromosomal rearrangements. c LINE-1 or L1-mediated retrotransposition. L1 retrotransposition can mediate the first-strand nick by the endonuclease, followed by first-strand cDNA synthesis with L1 mRNA as the template by reverse transcriptase. The cDNA negative-strand can invade a second 3′ overhang from a preexisting DSB and mediate the synthesis of the second-strand cDNA

Fig. 2

Roles of non-coding RNAs in structural variation. a dlincRNA-mediated DSB repair. After DSBs, RNA polymerase II (RNAPII) binds to the MRN complex and generates dilncRNAs, which are DDRNA precursors. Then, DDRNA pairs with nascent unprocessed single-stranded dilncRNAs, and they cooperate to bind to 53BP1 and fuel DNA damage response activation. b LncRNA can interact with multiple translocation partners. c RNAs are involved in the formation of chromatin loops through proper interaction with the RNA-binding region in CTCF. d The tapRNAs are co-expressed with their neighboring genes in a tissue-specific manner and they regulate genes by affecting topological conformations. e lncRNAs can modulate their target gene expression by promoting enhancer–promoter interactions. f RNAs interact with and recruit epigenome regulators such as components of PRC2 including EZH2 to the targeted locus, and then promote trimethylation of H3K27 in the targeted locus, thus inducing silencing of specific genes

Fig. 3

TAD and oncogene activation. a Hierarchical layers of chromatin organization. b–e Oncogene activation through different TAD rearrangements