New insights of extrachromosomal DNA in tumorigenesis and therapeutic resistance of cancer

Abstract

In the past few decades, the studies of extrachromosomal DNA (ecDNA), which existed independently of chromosomes, were tepid. However, recent studies on ecDNA rekindled the enthusiasm of oncologists for further studying ecDNA. In this review, we summarized the recent advances of ecDNA in oncogenesis and oncotherapy. ecDNA consists of highly open chromatin, and its circular structure enables ultra-long-range chromatin contacts. ecDNA is not inherited in accordance with Mendel's laws. Furthermore, ecDNA is widely existed in cancer cells, but almost never found in normal cells. It has been found that ecDNA played important roles in tumorigenesis and tumor progression, including oncogene amplification, tumor heterogeneity, enhancer hijacking and genomic rearrangement. More importantly, ecDNA is closely related to cancer treatment resistance. In hence, further understanding of ecDNA would contribute to developing innovative targeting ecDNA therapies.

Keywords: Extrachromosomal DNA; double minutes; therapeutic resistance; tumorigenesis.

Figure 1

Schematic diagram of hereditary differences between chromosome and ecDNA. When the oncogene is on a chromosome, the sister chromatids attached to the centromeres are equally divided into two daughter cells because of the pull of spindle fibers during mitosis, this is a classic Mendel’s law. But when the oncogene is located on ecDNA, the ecDNA replicates with the chromosome, the spindle fibers can’t hold on to it because there is no centromere, which leads to the ecDNAs after replication being randomly divided into two daughter cells during cell cleavage.

Figure 2

Prensence of ecDNA in human cancers. ecDNA is existed extensively in multiple cancers. In addition to glioblastoma, lung cancer, renal cancer, colon cancer and melanoma own ecDNA, men with prostate cancer and women with breast cancer or ovarian cancer also possess ecDNA.

Figure 3

Novel role of NHEJ in formation of ecDNA in therapeutic resistance of cancers. ecDNA-containing cancer cells express higher level of proteins associated with NHEJ, which can promote the repair of DNA double-strand break (DSB) induced by radiotherapy and chemotherapy, and then lead to the occurrence of therapeutic resistance. However, depletion or inhibition of DNA-PKcs, a key NHEJ protein, can cause the disappearance of ecDNA and the inhibition of DSB repair by NHEJ, thus increase cancer’s sensitivity to treatment and induce cancer cell apoptosis.

Figure 4

Functions of ecDNA in tumors. ecDNA plays important roles in tumorigenesis and tumor progression by virtue of several approaches, for example, ecDNA relieves heredity constraints and contributes to dynamic cancer evolution; enhancer hijacking and oncogene amplification of ecDNA can accelerate cancer development. Besides, ecDNA is an unanticipated major source of genomic rearrangements in cancer. More importantly, cancer cells potentially evade therapies that targeted oncogenes maintained on ecDNA by a highly specific, dynamic and adaptive pathway and thus induce treatment resistance.