Fusion gene: Is it a carcinogenic devil or a cancer angel?

Genes are the basic unit of genetic information. They carry the necessary information for constructing, maintaining, and repairing organisms. They also support the basic structure and performance of life, and store the race, blood type, growth, growth, and apoptosis of life. All the information that determines the intrinsic factors of life and health. Therefore, the author of the best-selling book Genes, oncologists, and well-known science writer Siddhartha Mujik called it the "source of all beings."

A few days ago, Nature Newsletter published a new study on fusion genes. Using CRISPR gene editing technology, the researchers revealed fusion gene types that are critical for cancer cell growth and discovered a new fusion gene that can be used for a variety of cancers, including brain and ovarian cancer. Provide new drug targets. The fusion gene is both a "devil" that causes tumors and an angel that targets cancer treatment.

Caused by chromosomal translocations, deletions, etc.

As the head of the Department of Oncology, Kunming Institute of Zoology, Chinese Academy of Sciences, Chen Ceshi, a researcher who found multiple candidate targets for breast cancer and other tumors, said in an interview with the Science and Technology Daily that there are about 20,000 different coding genes in the human genome. Under normal circumstances, they will perform different functions in an orderly manner. However, it has been found that when tumors occur, they are often accompanied by rupture and re-splicing at the genome level. When the coding regions of two or more genes are broken and linked to other genes, it is possible to form a new gene fragment under the same set of regulatory sequences, which is the fusion gene. Usually caused by chromosomal translocations, deletions, etc., usually, they lead to the production of a fusion protein that is a sequence or functional abnormal expression product.

As early as 2009, the University of Michigan's Comprehensive Cancer Research Center launched a relatively new gene detection technology at the time, where genes can be fused when chromosomes are put together. This fusion is thought to be the mechanism that leads to the formation of certain cancers. According to a study published in Nature, the discovery of this gene fusion may become a marker for cancer diagnosis or a target for future drug action. The researchers also identified several fusion proteins in prostate cancer cells, and these fusions were found only in cancer cells.

So far, about 20,000 fusion genes have been locked, but little is known about their exact function and role in cancer development. Therefore, it is of great clinical significance to distinguish whether fusion genes have an impact on cancer survival.

Tumor production, or due to genomic rearrangement

A long time ago, scientists observed the role of mitochondrial changes in cell "power plants" in cancer growth. In 2018, Nature published an important achievement at the Columbia University Medical Center. The fusion of two adjacent genes led to mitochondrial overactivation and increased the number of "fuels" that help cell growth, leading to cancer. The researchers also found that drugs targeting this newly discovered cancer pathway prevented tumor growth and were confirmed in human cancer cells and mice with brain cancer.

Chen Ceshi believes that the types of gene rearrangements that cause gene fusion mainly include balanced and unbalanced rearrangements. Balanced rearrangement is the most common way of gene fusion in cancer. After the rearrangement, the total number of chromosomes is not increased or decreased, but the structure is slightly changed. In addition, the non-equilibrium rearrangement refers to the change of the total number of chromosomes after gene rearrangement. Caused by factors such as gene deletion and duplication.

"The genomic rearrangement that causes gene fusion may lead to overexpression of the original gene, and secondly, it may lead to the formation of a novel function of the chimeric gene, which usually plays an important role in the early stages of cancer." Chen Ceshi introduced the BCR-ABL1 fusion oncogene causing acute lymphoblastic leukemia as an example. The long arm of chromosome 22 and the chromosome 9 translocated to form a new chromosome, resulting in rearrangement of related genes. This rearrangement method will BCR gene. A part of the 5'-end gene and a partial sequence of the 3' end of the ABL1 gene are joined together to form a new fusion protein, BCR-ABL1, which has strong tyrosine kinase activity and strong cancer-promoting function. Based on this, people have developed the targeted drug Gleevec, which is aimed at the fusion protein.

In the latest study, Columbia University Medical Center and its collaborators analyzed more than 8,000 fusion genes from more than 1,000 human cancer cell lines from 43 different cancer types. They found that 90% of fusion genes do not play an important role in cancer, but when inferring the cause of cancer from the genomic rearrangement of a patient's tumor, "these results should be considered."

Existing test methods coexist

A fusion gene usually connects the coding regions of two or more genes end to end to form a chimeric gene. According to the composition, there are both functional fusion of functional genes, study of their functions and characteristics, and efficient expression of the target gene by signal peptide or monomer sequence carrying the target gene, thereby enhancing the fusion of the target protein; Expand the integration of genetic applications.

Because of the discovery of fusion genes, it may become a target for the diagnosis of cancer or a drug. Therefore, fusion gene detection has practical significance for clinical diagnosis and prognosis of cancer, and can guide clinicians to develop scientific treatment plans to avoid undertreatment or over.

Chen Ceshi introduced that the gold standard for gene fusion detection is fluorescence in situ hybridization (FISH), which can detect the location of the target gene in the chromosome to determine whether there is genetic ectopic occurrence, but the experimental operation is complex and the technical requirements are high. Secondly, immunohistochemistry (IHC) is also one of the commonly used detection methods. It is a method for detecting the expression level of a target protein by using a specific antibody, and can display whether the target protein is expressed and whether the expression amount is changed. The disadvantage is that it is usually not directly detectable. The fusion gene has a strong subjectivity for the interpretation of the results; the third method is reverse transcription PCR (RT-PCR), which has the advantage of high operability. PCR primers designed for known fusion genes can be easily and quickly performed. Detection and judgment. These three techniques are only applicable to tumor tissue samples, which limits the expansion of the application, because many patients with advanced cancer cannot be surgically sampled, so these detection techniques cannot be used to detect the status of the fusion gene.

However, high-throughput sequencing (NGS) differs from microdroplet digital PCR (ddPCR) in that it can detect not only fusion genes in tissue samples, but also samples obtained by non-traumatic means such as plasma, and tumor fusion genes. Detection; NGS can also detect multiple genes and multiple fusion variants at one time, and find unknown mutations, but experimental operation and data analysis are time-consuming and require high samples; ddPCR is after the droplets are processed. PCR amplification is performed to detect multiple gene loci in a small number of samples. The disadvantage is that the unknown fusion gene cannot be detected.

Chen Ceshi believes that the detection methods of these fusion genes have their own advantages and disadvantages, and often need to combine multiple detection methods to make comprehensive judgments.