The Clinical Relevance of Fusion Genes

By Shivani Rajhansa

Deletions, duplications, inversions, and translocations in chromosome structure all represent chromosomal rearrangements in the genome. The genomic instability and mutagenic tendencies observed in many cancers may be a result such chromosomal rearrangements. These genomic changes are often associated with the altered expression of oncogenes or tumour suppressor genes, and the dysregulation and changes in transcription levels of such genes may provide a proliferative advantage. However, there is another oncogenic consequence of chromosomal rearrangements that is less discussed in literature: the formation of fusion genes (1). 

Fusion genes are a result of the aberrant joining of two genes which are then transcribed and translated as a single unit (2).  Inversions, tandem duplications, and chromosome deletions can all lead to fusion genes, but the most common mechanism is chromosomal translocation. The breakage of two chromosomes followed by the error-prone mechanism of non-homologous end-joining sometimes results in the joining of fragments from two different chromosomes (3).  The Philadelphia chromosome is an example of this abnormal event. There is a breakage in chromosomes 9 and 22 at particular sites. A chromosome 9 fragment and chromosome 22 fragment are wrongly fused by non-homologous end-joining. This results in the fusion of the ABL1 gene, originally on chromosome 22, and the breakpoint cluster region (BCR) gene, originally on chromosome 9. ABL1 codes for tyrosine protein kinase ABL1, while the function of the BCR protein is not entirely understood. When these genes are joined to form the BCR-ABL1 fusion gene, it results in the coding of a hybrid protein. The hybrid protein is a constitutively active tyrosine kinase. The discovery of the Philadelphia chromosome was the first example of a fusion gene playing a significant role in cancer genesis (4). In fact, this fusion is present in over 95% of chronic myeloid leukemia patients. The hybrid product, constitutively active tyrosine kinase, plays a key role in pathways involved in the proliferation and transformation of cancer cells (5). 

The Philadelphia chromosome is only one example of a fusion gene contributing to carcinogenesis. Several other fusions that lead to outcomes other than kinase fusions may also play a role in cancerous growths. The relevance of fusion genes in cancer research is both diagnostic and therapeutic. Cancer screening is often a difficult task, with many cancers not detected until later stages. Therefore, the opportunity to use simple molecular techniques like polymerase chain reaction (PCR) and immunohistochemistry to detect cancer is an exciting one (3). For example, BCR-ABL1-positive chronic myeloid leukemia can be detected by conventional cytogenetics via the Philadelphia chromosome, or the fusion gene can be detected by either fluorescent in situ hybridisation or by PCR (6). Other cancers known to be characterised by a certain fusion event could also be screened for through the aforementioned techniques. In fact, rhabdomyosarcomas, which have shared chromosomal rearrangements, are catagorised into fusion-positive and fusion-negative subtypes (3).

Fusion genes also represent a therapeutic target. The most clinically relevant gene fusion outcomes to target would be kinase fusions, transcription factor fusions, and loss-of-function fusions. The BCR-ABL1 kinase fusion is targeted by FDA-approved tyrosine kinase inhibitor, dasatinib. Other fusions that result in constitutively active kinases could also be targeted by similar inhibitors. In fact, there are around 400 known kinase fusions – such as ALK-ROS1-RET lineage, BRAF, NTRK and FGFR fusions – many of which could be inhibited by kinase inhibitors. An indirect method to target kinase fusions would by inhibiting heat shock protein 90 (HSP90). HSP90 is responsible for the folding and stabilisation of oncogenic proteins including kinase fusions (3). 

Transcription factor fusions produce hybrid proteins that act as abnormal transcription factors. For example, the fusion of EWS and FLI1 codes for a multimeric protein that reprograms gene regulatory circuits in Ewing sarcoma. It activates many downstream oncogenes, such as GLI1AURKACCK and FOXO1, which are being investigated as therapeutic targets. Drugs could also directly target the transcriptional activity of the hybrid transcription factor. Englerin A, for instance, is able to reduce the phosphorylation and binding ability of the EWS-FLI1 fusion transcription factor (3). 

Lastly, there are loss-of-function fusions, which could also be therapeutically targeted. These are fusions that lead to a loss of the original gene’s tumour suppressive roles.  In FGFR3–TACC3 fusion, there is a loss of the 3′-UTR of FGFR3, which contains the miR-99a regulatory region. This leads to an increased expression of FGFR3, and its oncogenic product promotes cell proliferation in cancer cells. The HSP90 inhibitor mentioned earlier has been shown to reduce levels of the hybrid product. This is likely because HSP90 is involved in the post-translational modifications and stabilisation of FGFR3 (3).

It has already been demonstrated that different gene fusions and the outcomes associated with them are an exploitable characteristic of many cancers. Ongoing research in this field, may give us insights into further targets for cancer therapy and a deeper understanding of the genetic aspects of carcinogenesis. 

References:

  1. Hasty P, Montagna C. Chromosomal rearrangements in cancer. Molecular and Cellular Oncology [Internet]. 2014;. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507279/ 
  2. Riggs P. Fusion Gene. [Internet]. 2013;:133. Available from: https://www.sciencedirect.com/science/article/pii/B9780123749840005647
  3. Dai X, Theobard R, Cheng H, Xing M, Zhang J. Fusion genes: A promising tool combating against cancer. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. 2018;1869(2):149-160.
  4. Kang Z, Liu Y, Xu L, Long Z, Huang D, Yang Y et al. The Philadelphia chromosome in leukemogenesis. Chinese Journal of Cancer. 2016;35(1).
  5. Salesse S, Verfaillie C. BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002;21(56):8547-8559.
  6. Tests for Chronic Myeloid Leukemia [Internet]. Cancer.org. 2018. Available from: https://www.cancer.org/cancer/chronic-myeloid-leukemia/detection-diagnosis-staging/how-diagnosed.html
  7. Dai X, Theobard R, Cheng H, Xing M, Zhang J. Fusion genes: A promising tool combating against cancer. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. 2018;1869(2):149-160.

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