ALK plays a major role in the development of the central and peripheral nervous systems. ALK promotes apoptosis in the absence of ligand binding and inhibits apoptosis in the presence of ligand binding (or ALK fusion protein). ALK abnormality is an important factor for the occurrence and development of tumors. Its abnormality mainly includes gene fusion, gene mutation, gene amplification and protein expression increase, among which gene fusion is the most common. ALK abnormality occurs in lymphoma, neuroblastoma, non-small cell lung cancer (NSCLC) and other tumors, and is the oncogenic driver gene of tumors.
3. ALK Gene Rearrangement and Tumor
ALK gene recombination can be used as a tumor driver . ALK induces the formation of malignant tumor phenotypes by promoting the activation of downstream signaling pathways and the proliferation of tumor cells. ALK gene recombination may be caused by double-stranded DNA break and abnormal DNA terminal connection . In general, different ALK fusion genes show differences in tumor transformation and tumorigenesis potential .
Figure 3 ALK gene rearrangement and cancer
3.1 Anaplastic Large Cell Lymphoma (ALCL)
ALCL is a type of malignant T-cell lymphoma expressing CD30. In most cases of ALCL, ALK is activated by rearrangement of chromosomes. NPM1-ALK is the most common translocation in ALCL, which is found in 75% ~ 80% of ALK-positive ALCL patients, followed by TPM3-ALK, which is found in 12% ~ 18% of ALCL patients. Other fusion proteins (TFG-ALK, CLTC1-ALK and ATIC-ALK) appeared less frequently.
3.2 ALK Positive Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is one of the most common malignant tumors in the world, with the mortality ranking the first among all malignant tumors, 85% of which are non-small cell lung cancer (NSCLC).
The ALK gene fusion mutation is a common driver gene for non-small cell lung cancer (NSCLC).Studies have shown that EML4-ALK fusion gene variation exists in non-small cell lung cancer (NSCLC) . EML4-ALK positive patients are mostly young people, and most of them are male patients. Patients who do not smoke or have a history of light smoking have a significantly higher positive rate than smokers .
At present, more than ten different EML4-ALK variants have been found in NSCLC, and other ALK-fused proteins, including SEC31A-ALK, HIP1-ALK, KIF5B-ALK and KLC1-ALK, are not common in lung cancer.
3.3 Inflammatory Myofibroblastic Tumors (IMTs)
Inflammatory myofibroblastic tumors (IMTs) are soft tissue stromal tumors. The TPM3/TPM4-ALK fusion gene is present in IMTs. Other genes fused to ALK (including TPM4, CLTC, CARS, and RANBP2) have a lower incidence in IMTs.
3.4 Neuroblastoma (NB)
Neuroblastoma is the most common extracranial solid tumor in infants and young children. It has a high degree of malignancy and is difficult to treat.
ALK is a susceptibility gene for clustering and sporadic NB, and participates in the pathogenesis of NB in both point mutation and amplification. Mutations in the ALK gene may be one of the factors in the poor prognosis of NB.
3.5 Other Rare ALK Positive Tumors
Recent studies have found that ALK abnormalities are also present in some common solid tumors.The study found that EML4-ALK gene fusion exists in both breast cancer and colon cancer .
Studies have reported multiple ALK fusions in patients with thyroid cancer (including EML4-ALK, GFPT1-ALK, TFG-ALK, and STRNALK) . At the same time, chimeric ALK protein expression was also found in thyroid cancer patients, and downstream AKT and ERK pathways were activated.
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