EWSR1::ATF1 Translocation: A Common Tumor Driver of Distinct Human Neoplasms

Abstract

Cancer is among the leading causes of mortality in developed countries due to limited available therapeutic modalities and high rate of morbidity. Although malignancies might show individual genetic landscapes, recurring aberrations in the neoplastic genome have been identified in the wide range of transformed cells. These include translocations of frequently affected loci of the human genetic material like the Ewing sarcoma breakpoint region 1 (EWSR1) of chromosome 22 that results in malignancies with mesodermal origin. These cytogenetic defects frequently result in the genesis of fusion genes involving EWSR1 and a number of genes from partner loci. One of these chromosomal rearrangements is the reciprocal translocation between the q13 and q12 loci of chromosome 12 and 22, respectively, that is believed to initiate cancer formation by the genesis of a novel, chimeric transcription factor provoking dysregulated gene expression. Since soft-tissue neoplasms carrying t(12;22)(q13;q12) have very poor prognosis and clinical modalities specifically targeting t(12;22)(q13;q12)-harboring cells are not available to date, understanding this DNA aberration is not only timely but urgent. Here, we review our current knowledge of human malignancies carrying the specific subset of EWSR1 rearrangements that leads to the expression of the EWSR1::ATF1 tumor-driver chimeric protein.

Keywords: Ewing sarcoma region 1; activating transcription factor 1; chimeric proteins; gene fusion; malignant mesothelioma; reciprocal chromosome translocation.

Figure 1

Structure of EWSR1. EWSR1 spans about 40 kb within the 12.2 locus of chromosome 22. It is most closely surrounded by genes in both forward and reverse orientations encoding nuclear proteins involved in interactions between chromosomes and the cytoskeleton (GAS2L1), and inhibition of cellular proliferation (RASL10A), as well as RHBDD3 that encodes an integral membrane protein predicted to be involved in protein metabolism. Its 17 exons generate a primary transcript that can give rise to various mature mRNAs by alternative splicing. Many of them, apparently, dictate translation of the corresponding polypeptides. The most well-documented alternative transcripts are depicted in the figure. Different colors of transcript variants represent spliced neighboring exons. The figure was created with Biorender.com.

Figure 2

Structure and functions of EWSR1. Wild-type EWSR1 has an N-terminal low complexity domain (LCD) that is mainly composed of serine–tyrosine–glycine–glutamine (SYGQ) repeats. The LCD is the subject of extensive post-translational glycosylations and phosphorylations. The C-terminal half consists of multiple domains that affect EWSR1 affinity to distinct nucleic acid species. These include three arginine–glycine–glycine-rich domains (RGG) flanking a conserved RNA recognition motif (RRM) and a zinc finger domain (ZF). The RRM consists of four anti-parallel β-strands and two α-helices arranged in a β-α-β-β-α-β fold with side chains that stack with RNA bases. Specificity of RNA binding is determined by multiple contacts with surrounding amino acids in the RGG and ZF domains [47]. These interactions are affected by multiple post-translation modifications of the RGG and ZF motifs including arginine methylations and lysine acetylations, respectively. The figure was created with Biorender.com.

Figure 3

Structure of ATF1. ATF1 spans about 57 kb along the plus strand of the q13.12 locus of chromosome 12. It is most closely surrounded by genes in similar forward orientations encoding a transmembrane serine protease (TMPRSS12) involved in the regulation of chromosomal synapsis formation and double-strand break repair, and DIP2B encoding a polypeptide that is predicted to participate in DNA methylation, up- and downstream, respectively. The seven exons of ATF1 generate a primary transcript that, via alternative splicing, can give rise to three protein-coding mature mRNAs (ATF1-201, -204 and 205) and a minimum of two additional transcripts (ATF1-202 and -203) that undergo nonsense mRNA-mediated decay. Different colors of transcript variants represent spliced neighboring exons. The figure was created with Biorender.com.

Figure 4

Variants of known EWSR1::ATF1 fusion transcripts found in clear cell carcinomas. Numbers indicate exons of EWSR1 and ATF1. Different colors of transcript variants represent spliced neighboring exons. The figure was created with Biorender.com.

Figure 5

Structure of the most common EWSR1::ATF1 in CCS. EWSR1::ATF1 contains the N- and C-terminal regions of EWSR1 and ATF1, respectively. Black numbers represent amino acids of the full-length chimera, color-coded numbers refer to the portions of EWSR1 (red) and ATF1 (blue) fused in the chimeric proteins. The figure was created with Biorender.com.