Trends in Cancer

Trends in Cancer

Volume 6, Issue 6, June 2020, Pages 462-477
Journal home page for Trends in Cancer

Opinion
Mechanisms Underlying Recurrent Genomic Amplification in Human Cancers

https://doi.org/10.1016/j.trecan.2020.02.019Get rights and content

Highlights

  • With the advent of genomic technologies, genomic regions of recurrent amplification in tumors have been mapped throughout the human genome. The mechanisms underlying such recurrence are of great interest.

  • Two mechanisms, breakage-fusion-bridge (BFB) cycles and the formation of double minute (DM) chromosome formation, have been and continue to be at the center of the topic for the past three decades. A common feature of these mechanisms is that, once the process is initiated, additional copy-number gain is streamlined.

  • BFB cycles can be initiated by the fusion of critically short telomeres and DNA breaks. A significant source of DNA breaks is replication stress.

  • DMs can be of both single-locus and multi-locus origin. Chromothripsis and erroneous DNA repair is a likely underlying mechanism.

  • The implications of both BFB cycles and DMs in the management of cancer patients have recently emerged.

Focal copy-number increases (genomic amplification) pinpoint oncogenic driver genes and therapeutic targets in cancer genomes. With the advent of genomic technologies, recurrent genomic amplification has been mapped throughout the genome. Recurrent amplification could be solely due to positive selection for the tumor-promoting effects of amplified gene products. Alternatively, recurrence could result from the susceptibility of the loci to amplification. Distinguishing between these possibilities requires a full understanding of the amplification mechanisms. Two mechanisms, the formation of double minute (DM) chromosomes and breakage–fusion–bridge (BFB) cycles, have been repeatedly linked to genomic amplification, and the impact of both mechanisms has been confirmed in cancer genomics data. We review the details of these mechanisms and discuss the mechanisms underlying recurrence.

Section snippets

Gene Amplification in Biology and Cancer

A gene can express its product robustly by increasing the copy number (gene amplification), and thereby accelerate a particular cellular activity. In somatic cell development, gene amplification is a regulated process to meet the increasing demands of protein synthesis (e.g., ribosomal RNA genes in Xenopus oocytes and ciliated protozoa) or of a particular protein that is necessary at a specific developmental stage (e.g., chorion genes in ovarian follicle cells in Drosophila) [1., 2., 3.]. Gene

Quests for the Underlying Amplification Mechanisms Using Mammalian Cell Models

Gene amplification in mammalian cells was first described as a cellular phenomenon that counteracts the increasing dosage of clastogenic drugs. Levels of the enzyme dihydrofolate reductase (DHFR) increase dramatically in mouse cells during stepwise selection with methotrexate (MTX), an inhibitor of DHFR. The increase of DHFR protein is associated with the multiplication (amplification) of the endogenous DHFR gene in a mouse sarcoma cell line [27]. This amplification was unstable and was lost in

Clinical Impact of Amplification Mechanisms

Having discovered two prevalent forms for the amplification of drug resistance genes in vitro, the chromosomal locations of naturally amplified oncogenes have been of great interest. In the 1980s, metaphases obtained from tumor cell lines were subjected to cytogenetic analysis and probed with known oncogenes. MYCN was the first gene demonstrated to be amplified in tumor cell lines. MYCN has homology to the MYC oncogene and was shown to be amplified in neuroblastomas in both DMs and HSRs [43,44

Cellular Processes Underlying Genomic Amplification

The formation of DMs and BFB cycles play crucial roles in both experimental gene amplification and cancer-driving gene amplification. An advantage in both mechanisms is that, once they are initiated, gaining additional gene copies is streamlined. Cells can accumulate additional DMs at each cell division by the unequal segregation of DMs. BFB cycles continue to distribute genetic material unequally to daughter nuclei by asymmetric breaks, one of which would gain additional copies. This review

Mechanisms of Genomic Amplification – BFB cycles

A classic model of genomic amplification mechanism is that a single DNA lesion initiates the process, and additional copies accumulate progressively over time in a stepwise manner. BFB cycles fit into this model. The initiating mechanisms for BFB cycles include dysfunctional telomeres [63], endonuclease-induced double-strand breaks (DSBs) [62,64], and drug-induced fragile sites [65] (Figure 2).

DMs of Mono-Locus Origin

Because the formation of DMs requires DNA rearrangements, mechanisms initiating BFB cycles (discussed above) such as replication stress could also underlie the formation of DMs. Several models have been proposed to explain how DMs arise (Figure 3). Earlier molecular and cytogenetic studies revealed that a chromosome break triggers the deletion of a chromosomal region that becomes a circular DNA [40,103]. By contrast, glioma cells harboring EGFR DMs retain EGFR gene copies at the native

Concluding Remarks

We focus here on two amplification mechanisms – DM formation and BFB cycles – that are strong candidate mechanisms for recurrent genomic amplification. A common feature of the two mechanisms is that, once they are initiated, the subsequent increase in copy number is streamlined. These mechanisms could also share the initiating events. For example, telomere–telomere fusion results in the formation of dicentric chromosomes that can provoke BFB cycles and chromothripsis [113]. Chromothripsis could

Acknowledgments

We would like to thank Drs Ryusuke Suzuki, Neeraj Joshi, and Michael Murata, as well as Ms Lila Mouakkad, for comments and edits on the manuscript. This work is supported by National Institutes of Health (NIH) National Cancer Institute (NCI) grant R01CA149385, Department of Defense W81XWH-18-1-0058, the Margie and Robert E. Petersen Foundation, and the Fashion Footwear Charitable Foundation of New York, Inc.

Glossary

Amplicons
a segment of DNA that is amplified as a result of genomic amplification.
Cytobands
cytogenetic bands. Each human chromosome has a short arm ('p' for petit) and long arm ('q' for queue), separated by a centromere. Each chromosome arm is divided into distinct cytogenetic bands that can be seen using a microscope and special stains.
FoSTeS/MMBIR
fork-stalling template switching/microhomology-mediated break-induced replication. A replication-based mechanism of genomic rearrangements that was

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