The ALK gene is associated with autosomal dominant neuroblastoma susceptibility.
At least 16 mutations in the ALK gene have been identified in some people with neuroblastoma, a type of cancerous tumor composed of immature nerve cells (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations in critical genes—those that control cell proliferation or differentiation—allows cells to grow and divide uncontrollably to form a tumor. In most cases, these genetic changes are acquired during a person's lifetime and are called somatic mutations. Somatic mutations are present only in certain cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent. Both types of mutation occur in neuroblastoma. Somatic mutations in the ALK gene occur during the development of some cases of sporadic neuroblastoma, and inherited mutations in the ALK gene increase the risk of developing familial neuroblastoma.
Mutations in the ALK gene change single protein building blocks (amino acids) in ALK receptor tyrosine kinase. The most common mutation in neuroblastoma replaces the amino acid arginine with the amino acid glutamine at position 1275 (written as Arg1275Gln or R1275Q). Arg1275Gln has been found in both familial and sporadic neuroblastoma and is the only common ALK gene mutation that has been found in both types of the condition.
Occasionally, extra copies of the ALK gene are found in people with neuroblastoma. This phenomenon, known as gene amplification, results in overexpression of ALK receptor tyrosine kinase.
Mutated or overexpressed ALK receptor tyrosine kinase no longer requires stimulation from outside the cell to be phosphorylated. As a result, the kinase and the downstream signaling pathway are constantly turned on (constitutively activated). Constitutive activation of ALK receptor tyrosine kinase may increase the proliferation of immature nerve cells, leading to neuroblastoma.
Normal Function of the ALK Gene
The ALK gene provides instructions for making a protein called ALK receptor tyrosine kinase, which is part of a family of proteins called receptor tyrosine kinases (RTKs). Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction.
Although the specific function of ALK receptor tyrosine kinase is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.