Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Abstract

Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

“…It is interesting to note that the transcriptome analysis detected the presence of a chimeric transcript encompassing KANK1 and DMRT1 exons, maybe reinforcing a modi ed product of KANK1 as a candidate for the phenotype. The role of chimeric transcripts as cause of congenital defects is poorly explored (Zuccherato et al 2016), in contrast to fusion transcripts commonly described as somatic events in cancer (Salokas, Dashi, and Varjosalo 2023). Only isolated cases were reported related to the detection of chimeric transcripts (gene fusions) as underlying molecular cause of developmental/neurological phenotypes (Boone et al 2014;Ferrari et al 2017).…”

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

“…It is interesting to note that the transcriptome analysis detected the presence of a chimeric transcript encompassing KANK1 and DMRT1 exons, maybe reinforcing a modified product of KANK1 as a candidate for the phenotype. The role of chimeric transcripts as cause of congenital defects is poorly explored ( Zuccherato et al 2016 ), in contrast to fusion transcripts commonly described as somatic events in cancer ( Salokas, Dashi, and Varjosalo 2023 ). Only isolated cases were reported related to the detection of chimeric transcripts (gene fusions) as underlying molecular cause of developmental/neurological phenotypes ( Boone et al 2014 ; Ferrari et al 2017 ).…”