Gene fusions are hybrid genes formed by the joining of parts of two or more original genes.
Gene fusions can occur due to chromosomal rearrangements such as translocations, deletions, inversions, or duplications.
Such events result in the creation of a novel gene that can produce a chimeric protein with altered or new functions.
Gene fusions can act as drivers of malignant transformation and cancer progression.
They are frequently observed in various cancers, including hematologic malignancies.
BCR-ABL1 in chronic myelogenous leukemia and solid tumor EWSR1-FLI1 in Ewing’s sarcoma) are examples.
Gene fusions can serve as diagnostic and prognostic biomarkers and are targets for molecular therapies.
Next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and reverse transcription-polymerase chain reaction (RT-PCR) are commonly used to detect these fusions in clinical settings.
Gene fusions are critical genomic events in cancer biology, providing insights into tumorigenesis and offering potential targets for therapeutic intervention.
They have been shown to act as drivers of malignant transformation and progression in many human cancers.
Fusion genes are also used as diagnostic and prognostic markers.
They help confirm cancer diagnosis and monitor response to molecular therapies.
Somatic fusion genes are one of the major drivers behind cancer initiation and progression.
A reciprocal translocation between the q-arms of chromosomes 9 and 22 was discovered in over 95% of chronic myelogenous leukemia patients.
The translocation was understood to produce a chimeric BCR-ABL1 transcript that encoded a constitutively active form of the ABL kinase
Burkitt’s lymphoma was found to harbor activating fusions between immunoglobulin genes and MYC
Among hematological malignancies, the identification of a PML-RARA fusion in acute promyelocytic leukemia paved the way for an effective tretinoin-based molecular therapy.
RUNX1-ETO chimeric protein is found to characterize a subtype of acute myeloid leukemia with prolonged median survival
Fusions between EWSR1 and members of the ETS transcription factor family in Ewing’s sarcoma.
SS18-SSX fusions in synovial sarcoma.
In myxoid liposarcoma, FUS-DDIT3 and EWSR1-DDIT3 fusions were found to be pathognomonic for the disease.
Fusion genes juxtaposing TMPRSS2 and members of the ETS transcription factor family are found in 70% of prostate cancers
EML4-ALK fusions and CHD7 rearrangements in non-small cell lung cancer.
KIAA1549-BRAF fusions in pediatric glioma.
FGFR3-TACC3 fusions in glioblastoma.
R-spondin fusions in colon cancer.
Some cancers are associated with multiple fusion genes that presented in a mutually exclusive manner.
The fusions TMPRSS2-ERG and TMPRSS2-ETV1 are common in prostate cancer, but almost never co-occur in a single tumor
The fusion genes SS18-SSX1 and SS18-SSX2 are found in 70% and 30% of synovial sarcoma patients, but never co-occur.
There is mutual exclusivity of ETS fusions and SPINK1 overexpression in prostate cancer
Fusion genes in human cancers.
ETV6-RUNX1 25% Interchromosomal translocation BCR-ABL1 15% Interchromosomal translocation Acute myeloid leukemia RUNX1-ETO 10–15% Interchromosomal translocation Acute promyelocytic leukemia PML-RARA 95% Interchromosomal translocation PLZF-RARA 0–5% Interchromosomal translocation Anaplastic large cell lymphoma NPM1-ALK 75% Interchromosomal translocation TPM3-ALK 15% Interchromosomal translocation Burkitt’s lymphoma IG@-MYC 90–100% Interchromosomal translocation Chronic myelogenous leukemia BCR-ABL1 95–100% Interchromosomal translocation Adenoid cystic carcinoma MYB-NFIB 90–100% Interchromosomal translocation Loss of microRNA regulation Bladder cancer FGFR3-TACC3 0–10% Tandem duplication
Clear cell sarcoma EWSR1-ATF1 90–100% Interchromosomal translocation Colon cancer PTPRK-RSPO3 5–10% Inversion Promoter exchange Congenital fibrosarcoma ETV6-NTRK3 90–100% Interchromosomal translocation Ewing sarcoma EWSR1-FLI1 90% Interchromosomal translocation
Follicular thyroid carcinoma PAX8-PPARG 60% Interchromosomal translocation Glioblastoma FGFR3-TACC3 0–5% Tandem duplication Oncogenic chimeric protein Inflammatory myofibroblastic tumor TPM3-ALK 50% Interchromosomal translocation Mucoepidermoid carcinoma MECT1-MAML2 60% Interchromosomal translocation Myxoid liposarcoma FUS-DDIT3 90–100% Interchromosomal translocation
EWSR1-DDIT3 0–5% Interchromosomal translocation Non-small cell lung cancer EML4-ALK 0–10% Inversion
NUT midline carcinoma BRD4-NUT 90–100% Interchromosomal translocation Papillary thyroid carcinoma CCDC6-RET 15% Inversion
NCOA4-RET 15% Complex rearrangement Pediatric renal cell carcinoma PRCC-TFE3 20–40% Interchromosomal translocation Pilocytic astrocytoma KIAA1549-BRAF 70%
Prostate cancer TMPRSS2-ERG 60% Deletion
Secretory breast carcinoma ETV6-NTRK3 90% Interchromosomal translocation
Serous ovarian cancer ESRRA-C11orf20 15% Intrachromosomal translocation
Synovial sarcoma SS18-SSX1 70% SS18-SSX2 30% Interchromosomal translocation SS18-SSX4 0–5% Interchromosomal translocation Some fusion genes are found in multiple cancers.
The BCR-ABL1 fusion gene is found recurrently in both chronic myelogenous leukemia and acute lymphocytic leukemia, and isolated cases have been reported in other leukemias.
TPM3-ALK fusions are found in 15% of cases of anaplastic large cell lymphoma, a hematological malignancy of T-cell origin and in 50% of inflammatory myofibroblastic tumors, solid cancers of myofibroblast origin.
EML4-ALK is found in in non-small cell lung cancer and NPM1-ALK in anaplastic large cell lymphoma.
Somatic fusion genes found in cancer Cells are excellent targets for therapeutics: treatment of BCR-ABL1 positive leukemia patients with the ABL kinase inhibitors,treatment of EML4-ALK positive non-small cell lung cancer patients with ALK inhibitor crizotinib.
Fusion genes are employed as diagnostic and prognostic markers.
Detection of BCR-ABL1 transcripts is used to confirm chronic myelogenous leukemia diagnoses, and transcript levels are followed throughout treatment to monitor for loss of therapeutic response.
Fusion genes can affect cell function through a number of mechanisms: Overexpression of an oncogene through promoter exchange, a fusion event;change the expression level of an oncogene by replacing its 3′-UTR, leading to altered regulation of the 5′ gene when the original 3′-UTR microRNA binding sites are lost; fusion genes can alter cellular function is through the formation of chimeric proteins.
Altered proteins may render a chimeric protein to activate alternative downstream targets, or sabotage a critical cellular function.
The autophosphorylated ALK kinases then activate oncogenic pathways such as the MAPK, JAK3-STAT3 and PI3K-AKT pathways.
In leukemias, BCR-ABL1 fusions constitutively activate the ABL1 kinase by enabling BCR-ABL1 oligomerization via the coiled coil domain present in BCR.
In glioblastoma, chimeric FGFR3-TACC3 proteins display constitutive phosphorylation and trigger aneuploidy by interfering with mitotic fidelity.
Not all fusion genes necessarily have biological impact.
The most common scenariofor a fusion gene to beg formed via somatic chromosomal rearrangement.
The four basic types of chromosomal rearrangement are deletions, translocations, tandem duplications, and inversions.
A fusion gene can arise via deletion when a genomic region between two genes located on the same strand is deleted.
The TMPRSS2-ERG fusion in prostate cancer is an example of a fusion that results from a 2.7 Mb deletion on chromosome 21.
Fusion genes can also arise from tandem duplication, a type of chromosomal rearrangement where a genomic region is duplicated one or more times, and the copies are tiled next to the original region.
Examples of fusion genes formed through tandem duplication include KIAA1549-BRAF fusions in pilocytic astrocytoma, FGFR3-TACC3 fusions in glioblastoma, and ALK fusions in colorectal cancer.
A tandem duplication or deletion is likely the cause when two genes located on the same chromosomal strand are fused.
In addition to chromosomal rearrangements involving genes on the same chromosome, some fusion genes involve genes located on separate chromosomes.
Such fusions involve the translocation of a small genomic fragment to a new locus, or a reciprocal translocation involving the swapping of entire chromosome arms.
Fusion genes caused by translocations include the BCR-ABL1 fusion, formed by a reciprocal translocation between 9q and 22q
The genomic breakpoints of fusion genes usually occur in intronic or intergenic regions, and rarely disrupt coding sequences.
A characteristic feature of many fusion-generating chromosomal rearrangements is the presence of sequence microhomology at rearrangement breakpoints.
A read-through fusion transcript occurs when an RNA polymerase continues transcribing beyond the end of a gene and transcription continues to an adjacent downstream gene.
Exon skipping can give rise to a fusion transcript encoding a functional chimeric protein.
Boxes indicate exons, thicker boxes indicate coding sequence.
Last and first exon skipping can also occur with fusion genes that arise from chromosomal rearrangements.
A chromosomal rearrangement with intergenic breakpoints can result in a fusion gene encoding a functional chimeric protein.
High throughput sequencing has transformed the field of cancer genomics by enabling affordable sequencing of entire cancer genomes and transcriptomes.
Current methods of high throughput sequencing are based on an approach where DNA is sheared into short fragments that are sequenced in millions of parallel chemical reactions.
Highly accurate instruments track the reactions and report them as millions of short nucleotide strings, also known as reads.
Computational algorithms are then used to assemble reads into longer contiguous sequences, quantify reads originating from different genomic regions, or identify evidence for putative genomic alterations.
Fusion genes arising from chromosomal rearrangements can also be identified using whole genome sequencing.
Some fusion genes are present in the germline of a subset of the human population.