Fusion genes, arising from chromosomal translocations through nonallelic homologous recombination (NAHR), are pivotal in oncogenesis, leading to the formation of fusion proteins that contribute to cancer’s aggressive nature. The atavism theory posits that cancer is a throwback to an ancient cellular state, with reactivated ancestral cellular mechanisms driving uncontrolled growth and other cancerous traits. By comparing the evolutionary ages of the structural homologs of fusion proteins with those of their parental gene pairs, this study aims to determine whether these fusion proteins recapitulate ancient protein structures, thereby supporting the atavism theory.Utilizing data from the COSMIC database, fusion genes were constructed according to their corresponding cDNA sequences from parent gene pairs, and the 3D structures of resultant fusion proteins were predicted by using AlphaFold. Subsequent VAST analysis identified structural homologies with ancient proteins. The ages of original and fusion proteins were inferred by mapping homologous groups from the Ensembl Compara database to identify common ancestors. The TimeTree database was then used to assign gene ages based on the divergence of the most distantly related species in these groups. Finally, comparing these ages identified ancestral resemblances. The findings of this project demonstrate homology between the structures of most fusion proteins and those of ancient proteins found in humans, yeast, and bacteria, suggesting the re-emergency of ancient protein structures in cancer cells due to recurrent translocations. (Permutation test, p=0.0201). Additionally, a large portion (68%) of the examined fusion genes comprises one gene predating the advent of multicellularity and another emerging concurrently with or after this evolutionary milestone (One-sample proportions test, X-squared=13.291, df=1, p=0.00027). These results support the atavism theory, suggesting that such fusion events might bridge evolutionary gaps between unicellular and multicellular life forms. This could potentially explain the mechanisms behind cancer’s tendency to forsake multicellular characteristics, thereby enhancing malignancy. By illustrating how chromosomal translocations in cancer might be tapping into primordial protein architectures, this study not only provides evidence for the atavism theory but also opens new avenues for understanding cancer’s evolutionary underpinnings. This could lead to novel therapeutic strategies by exploiting the ancient vulnerabilities revealed through chromosomal translocations.

ABSTRACT Genomes are biologically complex entities where an alteration in structure can yield no effect, or have a devastating effect on many pathways. Most of the focus has been on translocations that generate fusion proteins. However, this is only one of many outcomes. Recent work suggests alterations in topologically associated domains (TADs) can lead to changes in gene expression. It is hypothesized that alterations in genome structure can disrupt TADs leading to an alteration in the variability of gene expression within the contained gene expression neighborhood defined by the TAD. To test this hypothesis, variability of gene expression for genes contained within TADs between 37 cancer cell lines from the NCI-60 cell line panel was compared with normal expression data for the corresponding tissues of origin. Those results were correlated with the data on structural events within the NCI-60 cell lines that would disrupt a TAD. It was observed that 2.4% of the TADs displayed altered variance in gene expression when comparing cancer to normal tissue. Using array CGH data from the cancer cell lines to map breakpoints within TADS, it was discovered that altered variance is always associated with a TAD disrupted by a breakpoint, but a breakpoint within a TAD does not always lead to altered variance. TADs with altered variance in gene expression were no different in size than those without altered variance. There is evidence of recurrent pan-cancer alteration in variance for eleven genes within two TADs on two chromosomes (Chromosome 10 & 19) for all 37 cell lines. The genes located within these TADs are enriched in pathways related to RNA processing. This study supports altered variance as a signal of a breakpoint with a functional consequence.