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Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure 123 and the evolutionary trajectories 4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism—which we term translocation—bridge amplification—involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage.
In breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs.
Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations.
A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage—fusion—bridge cycle prevalent in some and the translocation—bridge amplification in others, probably owing to the different timing of DNA break repair.
Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer. Copy-number amplification is a common mode of oncogene activation in cancer 1. In contrast to large-scale copy-number gains such as chromosome arm-scale aneuploidies, oncogene amplifications are frequently focal with high amplitude 56suggesting distinct causal mechanisms.
Previous work has established that cancer cells can östrogen receptor nedbrytande behandling different evolutionary paths to acquire high-level copy-number amplification. In some cases, the oncogenes are linearly amplified after a single DNA double-strand break DSB through the breakage—fusion—bridge BFB cycle 2 —iterative cycles of chromosome breakage, DNA replication, sister chromatid fusion and dicentric chromosome bridge formation that results in another breakage.
More recently, it was shown that high-level amplifications can also originate from chromothripsis, the phenomenon of massive chromosomal fragmentation and rearrangement, through the formation of extrachromosomal circular DNAs 37891011 ecDNAs. Despite these advances, the initial mutational events leading to focal oncogene amplifications remain poorly understood.
Breast cancer is one of the cancer types in which the focal amplification of oncogenes has a crucial role in oncogenesis These focal amplifications typically occur early in breast oncogenesis, probably contributing to the transition from atypical ductal hyperplasia to ductal carcinoma in situ 16 Late emergence of focal amplifications during treatment has also been reported 18suggesting their relationship to the on-going mutational processes in cancer cells.
Despite the importance of focal amplifications in breast cancer, how the cell of origin acquires the amplicons and whether this process is associated with risk factors for breast cancer have remained unclear. Here we identify a mechanism initiating focal amplification in breast cancer by analysing whole-genome sequencing WGSRNA sequencing and epigenomic data.
Through bioinformatic analysis and experimental validation, we show that oestrogen-induced DNA breaks and their repair by inter-chromosomal translocations initiate a cascade of events leading to focal oncogene amplification.