What is a " jumping gene"

Also known as transposons, genetic material that can replicate itself and move between chromosomes. They have the potential to disrupt the structure of the genes involved, and are considered to be the fundamental reason for the gradual change of biological genes, which ultimately promotes biological evolution. While organisms like yeast have only a few dozen jumping genes, mammals typically contain hundreds of thousands of jumping gene DNA, making it difficult to tell where, when, or even if jumping occurred.

Just as Legos can be arranged in new ways to build various structures, genetic elements can be mixed and matched to make new genes, according to a new study. The research results were published in the journal Science on February 19, 2021, with the title "Recurrent evolution of vertebrate transcription factors by transposase capture".

A long-proposed mechanism for making new genes, called exon shuffling, works by recombining functional blocks of DNA sequences into new genes that express proteins.

The new study investigates how genetic elements called transposons, or "jumping genes," have been mixed in during evolution to assemble new genes through exon shuffling. The final research conclusion: Exon shuffling is an important evolutionary force for generating genetic novelty.

The progress of gene jumping can increase the function of proteins and promote the evolution of organisms, but the loss of gene jumping can also bring a fatal blow. In human cancer-related research, there is a phenomenon called "exon skipping", and more than half of diseases caused by single nucleotide mutations in the coding region of genes affect RNA splicing. These mutations result in the deletion of exons from the gene, a phenomenon known as exon skipping. Typically, transcriptional deletion caused by MET gene exon 14 splice site mutation occurs in 3% to 4% of NSCLC (non-small cell lung cancer) patients, which is one of the common driver genes in NSCLC patients.

The MET gene is located on the long arm of human chromosome 7 and contains 21 exons. The c-Met protein encoded by the MET gene is a tyrosine kinase receptor for hepatocyte growth factor (HGF). The combination of HGF and c-Met activates downstream signaling pathways to promote cell proliferation, growth, migration, and angiogenesis. When the MET gene is abnormal, it can drive tumor growth by increasing cell proliferation, survival, invasion and metastasis.

Molecularly, the transcriptional deletion of MET14 exon caused by MET splice site alterations, including point mutations, insertions or deletions, and large-scale exon deletions, can lead to dysregulation of MET. These changes spatially perturb the splice acceptor or donor flanking the MET14 exon. The MET14 exon skipping mutation occurs in the juxtamembrane domain of MET. Since this region contains the CBL (an E3 ubiquitinase) and Y1003 binding site, deletion of this site can lead to impaired MET ubiquitination and reduced MET degradation, thereby reducing MET degradation， enhances MET signaling to increase cell proliferation, survival, invasion and metastasis to drive tumor growth.

Detection of MET exon 14 skipping mutations, including direct detection of MET exon 14 mRNA by NGS or qRT PCR, or NGS detection at the DNA level for genetic variants that may lead to MET exon 14 splicing.

The first targeted drug in China to treat MET-14 mutant lung cancer

On June 22, 2021, China's National Medical Products Administration (NMPA) approved the innovative targeted drug jointly developed by AstraZeneca and Chi-Med Pharmaceuticals - the MET inhibitor savolitinib (Vorisha, savolitinib, formerly known as : savolitinib) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations. This is the first approved highly selective MET inhibitor in China. Therefore, the approval of sevolitinib officially opened a new era of MET-targeted therapy for cancer in China, filling the gap in which there is no drug available for such patients in China.

MET testing needs to follow guideline recommendations. The NCCN guidelines recommend MET exon 14 skipping mutations as a routine recommendation and MET amplification as an emerging biomarker recommendation.

Currently, NGS is probably the most commonly used detection technique. Clinically, the incidence of MET exon 14 skipping mutation is only about 3%. For this rare mutation, we often perform parallel detection with other genes, especially under the premise that the current clinical samples are relatively small, it is difficult to perform one by one. Therefore, multi-gene testing at one time is very beneficial for patients with MET exon 14 skipping mutations, and it can also save clinical specimens.