Nature: Oncogene “Seismic Amplification” drives many kinds of cancers!
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Nature: Oncogene “Seismic Amplification” drives many kinds of cancers!
Extrachromosomal DNA (ecDNA) is a special type of circular DNA that is free from the chromosome and falls off the normal genome.
As early as 1964, people observed the existence of ecDNA in neuroblastoma cells[1, 2], but due to technical limitations, people failed to have a better understanding of the specific role of ecDNA in tumorigenesis and development.
In 2017, Paul Mischel’s team published an article in “Nature” to prove that
ecDNA is widely present in nearly half of human tumor cells, and ecDNA without centromere sequence is unequally distributed during mitosis.
Greatly accelerate the formation of tumor heterogeneity [3].
Two years later, Paul Mischel’s team once again published a research paper in the journal Nature, proving that ecDNA has a highly open chromatin structure, and the oncogene on ecDNA showed a significantly higher expression level [4]. So far, ecDNA has attracted widespread attention.
There are many hypotheses about the origin of ecDNA in tumor cells, such as tandem replication model, broken fusion bridge model (BFB), chromosome fragmentation model (chromothripsis), etc. However, the current comprehensive analysis of the structure of ecDNA shows that the production process of ecDNA should be a more complicated process, not just caused by a single factor .
Recently, Professor Matthias Fischer from Children’s Hospital of the University of Cologne in Germany published an important study results in “Nature Genetics”, this study shows us a new by the “Seismic amplification” (due to the complexity of the number of copies The amplification pattern is similar to seismic waves, so it is named seismic amplification), which provides new insights into the origin of ecDNA in cancer cells [5].
Screenshot of the paper’s homepage
Gene copy number amplification plays a very important role in the occurrence and development of cancer.
In addition to the amplification that occurs on the chromosome, a considerable number of genes are amplified in the form of ecDNA.
The existence of ecDNA greatly increases the complexity of the tumor genome. Neuroblastoma is a type of tumor that occurs more often in children.
Previous studies have shown that about 20% of neuroblastomas have copy number amplification of the MYCN gene [3], The vast majority (93%) of these amplifications occurred on ecDNA .
In order to better understand the mechanisms by which these types of amplification occur, the Fisher team conducted this study.
First, the Fischer team conducted a genome-wide analysis of 79 neuroblastoma samples, and found that some sites where the copy number was amplified showed a completely different amplification pattern from other regions. The sites in these regions have 14 sites.
More than one copy number is amplified, and large-scale internal or inter-fragment rearrangement occurs.
Figure 1: (a) Seismic amplification presents a significantly different pattern from other amplification methods (large number of rearrangements and higher copy number)
Since the schematic diagram of this amplification mode is similar to seismic waves , the Fischer team defined this amplification mode as seismic amplification .
Through statistical analysis of the ecDNA generated in the form of seismic amplification in the samples, the Fischer team found that 19 out of 79 samples had seismic amplification.
Subsequently, the Fischer team analyzed the specific sites where the seismic amplification occurred and found that seismic amplification mainly occurred in two hot spots, one of which was located on chromosome 2p24 (covering MYCN locus) , and the other was located at 12q13 and 12q15 sites (covering CDK4 and MDM2 sites) .
In the 4 cases, the amplified regions of 2p and 12q were connected to each other by rearrangement, indicating that this form of seismic amplification had co-amplification in the same case.
Figure 2: Oncogenes most frequently amplified on ecDNA[6]
Since it was observed that genes enriched in ecDNA such as MYCN frequently appeared at seismic amplification sites, Fischer’s team analyzed the location of these seismic amplification sites in cells.
The FISH results showed that seismic amplification in cells is mainly based on three There are two forms: DM (double minutes, the old name of ecDNA) , HSR (the structure formed by the reintegration of ecDNA into the chromosome) , and NC (neochromosomes, a type of abnormal chromosomes present in cancer cells) .
Figure 3: In tumor cells, seismic amplification sites mainly exist in three forms (DM, HSR, NC)
In order to prove that seismic amplification is not a unique phenomenon in gliomas, Fischer’s team further performed a genome-wide analysis of 2,677 samples of 37 cancers in the pan-cancer database and identified 9127 amplifications with a copy number of 5 or more.
Among them, 284 amplicons in 255 cases (9.5%) were classified as seismic amplification sites according to the previous definition .
Among them, about 95% of the sites were not clearly classified in previous studies. , Which suggests that seismic amplification may define a unique type of structural change in cancer .
In addition, statistical analysis results show that seismic amplification has obvious tissue specificity, with the highest incidence in high-grade glioma (34.2%), osteosarcoma (26.5%) and several other cancers , while in lymphoma, Leukemia and benign tumors are almost non-existent (Figure a below).
Compared with other amplification modes, seismic amplification has a higher level of amplification and rearrangement, a wider chromosome coverage area and a longer amplified fragment length (Figure b below).
Figure 4: (a) Analysis of seismic amplification sites in pan-cancer (b) Comparison of seismic amplification and other amplification forms
Considering that previous studies have shown that chromosome fragmentation in tumor cells is one of the reasons for the production of ecDNA[7], and chromosome fragmentation events will also cause a large number of rearrangements between chromosome fragments, therefore, the team speculated that chromosome fragmentation may be possible It is one of the initial events that drove the earthquake amplification.
In order to verify this hypothesis, the team compared the chromosome fragmentation event site with the seismic amplification site, and found that 77.6% of the seismic amplicons partially overlap with the chromosome fragmentation site, of which 34.9% The complete overlap of the loci indicates that there is indeed a certain relationship between chromosome fragmentation and the occurrence of seismic amplification.
Figure 5: Comparison of seismic amplification sites and chromothripsis sites
However, although chromosome fragmentation can promote the process of a large number of gene rearrangements, the process itself does not cause a large number of copies of fragments to be amplified (Figure 1b), and the copy number of seismic amplification sites is significantly higher than other sites.
Amplification sites , so there must be other processes that promote a sharp increase in the copy number of seismic amplification sites.
Previous studies have shown that the BFB process can lead to the gradual amplification of the genome, and the BFB process is accompanied by the enrichment of a large number of reverse-folded sequences.
After comparison, the number of inverted fold sequences in seismic amplification sites is much lower than other forms of amplification, indicating that there are other forms of copy number amplification processes in the formation of seismic amplification patterns .
Therefore, the team developed a circular recombination model (as shown in Figure a below).
Through odd or even recombination processes, similar gene rearrangement patterns at seismic amplification sites can be generated.
Figure 6: Schematic diagram of circular recombination model
In order to more accurately measure the contribution of the BFB or circular recombination process in the formation of the seismic amplification mode, the team simulated three situations with a computer:
(1) BFB after chromosome fragmentation,
(2) after BFB Fragmentation of chromosomes occurs,
(3) Circular recombination occurs after fragmentation of chromosomes.
After comparison, it is found that the simulation results of the third case are more consistent with the pattern of seismic amplification sites.
Based on the above facts, the team proposed a model to generate ecDNA through seismic amplification:
- One or more chromosomes undergo a chromosomal fragmentation event to produce fragmented DNA.
- One or more chromosomal fragments are integrated into a circular ecDNA form.
- ecDNA undergoes circular recombination.
- The amplified fragment may continue to exist in the form of ecDNA, or it may exist stably through integration into the chromosome to form an HSR region.
Figure 7: The process of generating ecDNA by seismic amplification
In summary, this article clarifies a new mechanism for generating ecDNA by seismic amplification. This amplification method has a more frequent rearrangement process and a higher copy number, and leads to more complex and variable chromatin. Structure, this research provides new insights for people to better understand the evolution of cancer genome.
It is worth mentioning that the Cancer Grand Challenges program of the National Cancer Institute and Cancer Research UK has listed ecDNA research as nine directions that must be overcome in future cancer research. one. In addition, some large biological companies have also started research on ecDNA-based cancer therapies. It is believed that as people’s research on ecDNA becomes more and more in-depth in the future, humans will definitely be able to better understand and overcome cancer.
References:
1. YOUNG CW, HODAS S. HYDROXYUREA: INHIBITORY EFFECT ON DNA METABOLISM. Science. 1964;146(3648):1172-1174.
2. COX D, YUNCKEN C, SPRIGGS AI. MINUTE CHROMATIN BODIES IN MALIGNANT TUMOURS OF CHILDHOOD. Lancet. 1965;1(7402):55-58.
3. Turner KM, Deshpande V, Beyter D, et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature. 2017;543（7643):122-125.
4. Wu S, Turner KM, Nguyen N, et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature. 2019;575(7784):699-703.
5. Rosswog C, Bartenhagen C, Welte A, et al. Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nat Genet. 2021;10.1038/s41588-021-00951-7.
6. Kim H, Nguyen NP, Turner K, et al. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat Genet. 2020;52(9):891-897.
7. Zhang CZ, Spektor A, Cornils H, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522(7555):179-184.
Nature: Oncogene “Seismic Amplification” drives many kinds of cancers!
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