Abstract
Circular extrachromosomal DNA (ecDNA) amplifications promote tumor heterogeneity and evolution.
Major finding: Circular extrachromosomal DNA (ecDNA) amplifications promote tumor heterogeneity and evolution.
Concept: ecDNA is detected in nearly half of human cancers but rarely in normal cells.
Impact: Tumor heterogeneity introduced by ecDNA amplifications may allow tumor cells to adapt to maximize survival.
Genomic amplifications in cancer can occur in chromosomes or in circular extrachromosomal DNA (ecDNA). However, ecDNA has not been well quantified in cancer, in part due to a lack of methods for analysis, and the oncogenes targeted by ecDNA amplification have not been determined. Turner, Deshpande, Beyter, and colleagues developed ECdetect, an image analysis software package, to quantify ecDNA in DAPI-stained metaphases. Integration of whole-genome sequencing data from 117 cancer cell lines and tumors, with bioinformatic and cytogenetic analysis of 2,049 metaphase cells from 72 cancer cell samples and 233 metaphase cells from normal tissues, revealed that ecDNA was abundant in cancer cells, found in nearly half of tumor samples from 17 different cancer types, but rarely detected in normal cells. The ecDNA level varied among tumor types and between cells within a tumor culture. Amplified oncogenes detected by whole-genome sequencing were found either exclusively in the ecDNA or in both the ecDNA and chromosomal DNA, and ecDNA amplification increased expression of the corresponding mRNA transcript. ecDNA is prone to unequal segregation to daughter cells, suggesting that it may induce a rapid genetic heterogeneity. Indeed, mathematical modeling indicated that ecDNA oncogene amplifications resulted in higher copy number than chromosomal oncogene amplifications, which was predicted to result in increased intratumor heterogeneity. Further, experimental data confirmed that ecDNA was associated with higher heterogeneity, validating the predictions of the model. The finding that ecDNA amplifications can promote expression of key driver oncogenes suggests that ecDNA may contribute to tumor progression and drug resistance. Further, these results define a role for ecDNA in accelerating intratumor heterogeneity, which may accelerate tumor cell evolution.
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 http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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