Abstract
Translocation of estrogen receptor target regions initiates focal amplification in breast cancer.
Major Finding: Translocation of estrogen receptor target regions initiates focal amplification in breast cancer.
Concept: Inter-chromosomal translocations lead to a chromosome bridge that fragments and enables amplification.
Impact: This study proposes a translocation–bridge model as a common mechanism of amplification in cancer.
Copy-number aberrations within human tumors can induce the overexpression of oncogenes and arise through genomic events such as focal copy-number amplification. Breast cancers frequently exhibit high-level focal amplification of oncogenes such as ERBB2 and CCND1, but the initial mutational events that lead to focal amplification are not completely understood. To investigate the origins of focal oncogene amplification, Lee and colleagues analyzed whole-genome sequencing data from 780 breast tumors and demonstrated that focal amplifications of ERBB2, CCND1, ZNF703, and ZNF217 were often connected to each other by inter-chromosomal translocations, suggesting that inter-chromosomal rearrangements may precede focal amplification. Indeed, structural variants flanked the boundaries of the majority of amplified regions, and oncogenes appeared to be frequently co-amplified in pairs that reflected recurrent translocations between specific genomic regions. Reconstruction of the complex rearrangements that likely generated focal amplifications in several patients revealed that amplifications often followed a model in which the translocation of one oncogene-containing region to another oncogene-containing region on a different chromosome during G1 of the cell cycle led to the formation of a chromosome bearing two centromeres. This is distinct from the well-known breakage-fusion-bridge cycle, in which double-strand break (DSB) is repaired in G2 by fusion between sister chromatids and only involves a single chromosome. Failure of the dicentric chromosome to separate during mitosis resulted in the generation of a chromosome bridge that subsequently fragmented into extrachromosomal DNA and facilitated amplification. This “translocation–bridge” model of focal amplification occurred in regions associated with estrogen receptor-α (ERα) binding after estradiol treatment, and genome-wide profiling of DNA double-strand breaks indicated that estradiol treatment induced genomic fragility and increased the translocation of ERα targets, suggesting that the repair of estrogen-mediated DSBs may trigger focal amplification. Classification of structural variants at the boundaries of focal amplifications across 38 tumor types highlighted a tissue-specific bias for different mechanisms of focal amplification, with translocation–bridge amplification predominant in liposarcomas, melanomas, and adenocarcinomas of the lung and breast. Overall, these findings uncover a common mechanism of focal amplification and propose that estrogen may induce the initial translocations that enable amplification in breast cancer.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/CDNews.
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