What Is an ALK Gene?
ALK (anaplastic lymphoma kinase) gene is a gene that synthesizes a protein that is required for cellular growth. Mutated (altered) forms of the ALK gene and protein have been associated with certain types of cancer, such as non-small cell lung cancer, neuroblastoma, and anaplastic large cell lymphoma. These mutations or alterations might lead to an increase in the growth of cancerous cells. Evaluating the ALK gene in tumor tissues might help plan cancer treatment.
What Is the Function of an ALK Gene?
The ALK gene has instructions for synthesizing the protein ALK receptor tyrosine kinase. The ALK tyrosine kinase belongs to a receptor tyrosine kinases (RTKs) protein group. Tyrosine kinases receptor transmits the signals from the surface of the cells surface within the cell through a process known as signal transduction. This process starts with stimulating the kinase on the cellular surface and then attaching it to an analog kinase. After this process, the kinase is tagged with a marker which is a group of phosphorous and oxygen atoms; this process is called phosphorylation. Phosphorylation activates the kinase protein. This activated kinase transfers a phosphate group to another protein within the cell, activating it. These activation pathways are essential in many cellular processes like cellular growth, division, and maturation. Although the exact function of the ALK receptor tyrosine kinase is unknown, it is thought to help regulate and proliferate nerve cells.
What Are the Various Types of ALK-mutated Tumors?
The different ALK-mutated tumors are as follows:
1) Neuroblastoma:
Neuroblastoma is a cancerous growth developing from immature nerve cells in various body parts. However, the areas in and around the adrenal glands often give rise to neuroblastomas, as these originate the same as the nerve cells and are placed at the top of the kidneys. In neuroblastoma, around 16 gene mutations of the ALK gene have been found. Cancer occurs due to an accumulation of genetic mutations in important genes that control cell growth and division, thus causing uncontrolled cell growth and division to form a tumor. In many instances, such mutations are acquired during the lifespan and are known as somatic mutations. Somatic mutations are present in cells that are not inherited during birth. Very few genetic mutations can be inherited from a parent. Both mutations cause neuroblastoma. Sporadic neuroblastoma is caused by somatic mutations in the ALK gene, whereas inherited mutations in the ALK gene cause familial neuroblastoma.
The mutations or alterations in the ALK gene change the building blocks of the proteins (amino acids) into ALK receptor tyrosine kinase. The genetic mutation in neuroblastoma substitutes the amino acid arginine with the amino acid glutamine at a particular position. This has been found in both sporadic and familial neuroblastoma, which is and is the only common ALK gene mutation. Sometimes, additional copies of the ALK gene are found in a few individuals with neuroblastoma. This process is known as gene amplification, which leads to the formation of excess copies of the ALK receptor tyrosine kinase protein.
Altered or excess ALK receptor tyrosine kinase dose nor need any stimulation to phosphorylate. Due to this, the kinase and the signaling pathway are constantly activated. This continuous activation of the ALK receptor tyrosine kinase increases the proliferation of immature nerve cells, causing neuroblastoma.
2) Lung Cancer:
Lung cancer is cancer with uncontrollable growth and multiplication of the lung cells forming a tumor. Lung cancer might not be detectable in its early stages. The symptoms include recurrent coughing, chest pain, breathing problems, blood in the mucus, difficulty in swallowing or speaking, loss of appetite, weight loss, exhaustion, or swollen face and neck. If cancer metastasizes or spreads to other organs, other symptoms might develop. Lung cancer occurs mostly in older adults. Many individuals with lung cancer have a history of smoking. However, it can also occur in individuals who do not have any history of smoking.
Lung cancer is usually divided into two types, non-small lung cancer and small cell lung cancer, based on the size of the cells. The spread of small cell lung cancer is quick, and by the time the condition is diagnosed, it has already spread out of the lungs to the other organs such as the adrenal glands, brain, liver, and bones. The survival rate of small cell lung cancer is less than non-small cell lung cancer.
Non-small cell lung cancer is further classified as adenocarcinoma, large cell lung carcinoma, and squamous cell carcinoma. Adenocarcinoma arises from the cells lining the air sacs located all over the lungs. Large cell carcinoma arises from cells lining the lungs. Large cell carcinoma includes non-small cell lung cancers which are not adenocarcinomas or squamous cell carcinomas. Squamous cell carcinomas arise from cells lining the tract from the windpipe to the lungs.
Inversion is another type of change that happens when chromosome 2 is split into two places, and the resulting DNA piece is reversed and re-inserted into the chromosome. Few people with non-small cell lung cancer have an inversion of chromosome 2. The fused proteins formed as a result of these rearranged genes function both as ALK receptor tyrosine kinase and the other partner protein. The fusion protein and signaling pathways get activated, increasing the growth of immature nerve cells and leading to cancer formation.
3) Other Tumors:
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Large Cell Lymphoma
ALK-mutated genes cause other types of tumors by changing the genes on chromosome 2. These changes are usually acquired during the lifetime and are present only in the cancerous cells. One such change is known as translocation, which exchanges the genetic material between chromosome 2 and other chromosomes. A couple of ALK gene translocations have been found in people with large-cell lymphoma, a rare type of cancer involving the T cells of the immune system. This translocation causes the fusion of the ALK gene with the NPM gene resulting in the formation of a protein called NPM-ALK. The NPM gene is the gene that gives instructions for synthesizing a protein within the cell's nucleus (part of the cell containing the genetic material).
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Inflammatory Myofibroblastic Tumor (IMT)
An inflammatory myofibroblastic tumor is a rare type of cancer with a tumor consisting of inflammatory cells and cells that play a part in wound healing (myofibroblasts). Seven translocations of the ALK gene have been identified in an inflammatory myofibroblastic tumor.
How Are ALK-mutated Tumors Treated?
Individuals with ALK-mediated tumors are likely to be prescribed the following ALK inhibitor drugs:
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Crizotinib.
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Ceritinib.
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Brigatinib.
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Lorlatinib.
After a few years, the ALK inhibitors cannot control cancer. During such a situation, the doctor might advise the following:
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Another ALK inhibitor after a re-biopsy to determine whether a specific ALK- resistance mutation has occurred to guide the choice of inhibitor.
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Increase the dose of the existing ALK inhibitor.
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Pemetrexed-based chemotherapy, particularly for ALK-positive cancers.
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Radiation therapy.
Conclusion:
ALK is anaplastic lymphoma kinase. Originally described in lymphoma, most ALK-positive cancers are found in non-small cell lung cancers. The ALK gene is present in the embryo. It helps in the developmental process of the nervous system and the gut. In some individuals, it activates and joins with another gene. This genetic fusion is called an ALK fusion or ALK rearrangement, which can lead to cancer. When ALK joins with another gene and causes any cancer, the individual is called ALK-positive. The most common fusion of the ALK gene is EML4. Even within EML4, There are different types of fusions depending on the position of the exact fusion of ALK with the gene. The treatment is the same for most ALK-positive individuals.
