Cancer accounted for 10 million deaths in 2020, nearly one in every six deaths annually. Despite advancements, the contemporary clinical management of human neoplasms faces a number of challenges. Surgical removal of tumor tissues is often not possible technically, while radiation and chemotherapy pose the risk of damaging healthy cells, tissues, and organs, presenting complex clinical challenges. These require a paradigm shift in developing new therapeutic modalities moving towards a more personalized and targeted approach. The tumor-agnostic philosophy, one of these new modalities, focuses on characteristic molecular signatures of transformed cells independently of their traditional histopathological classification. These include commonly occurring DNA aberrations in cancer cells, shared metabolic features of their homeostasis or immune evasion measures of the tumor tissues. The first dedicated, FDA-approved tumor-agnostic agent’s profound progression-free survival of 78% in mismatch repair-deficient colorectal cancer paved the way for the accelerated FDA approvals of novel tumor-agnostic therapeutic compounds. Here, we review the historical background, current status, and future perspectives of this new era of clinical oncology.

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.