The ALK gene, previously known as anaplastic lymphoma kinase, was discovered in 1997 in parallel by two research groups, Shiota et al. [citation] and Morris et al. [citation]. Shiota et al. group studied Ki-1 lymphoma cell line, AMS3, and found a novel protein called - p80 tyrosine phosphoprotein. Morris et al. described a novel protein tyrosine kinase gene.
Where is the ALK gene found? On what chromosome is the ALK gene located?
Humans have 46 chromosomes in total, which harbor genes at specific locations. Each chromosome has two separate sections called arms: a longer q arm and a shorter p arm. In this case, the ALK gene location is on the shorter p arm of chromosome 2, more precisely in positions 23.2-23.1[citation].
How long is the ALK gene? What does the ALK gene encode? What does the ALK tyrosine kinase receptor do?
ALK gene has 29 exons (exons are part of the gene which encode proteins) encoding a protein of 1620 aminoacids [citation].
As with most the genes, the ALK gene also encodes a protein, and in the case of the ALK gene, the protein is called anaplastic lymphoma kinase (ALK) or ALK tyrosine kinase receptor (also known as CD246) [citation]
Each cell has proteins called transmembrane receptors that pass through the cell membrane from one side to another. The ALK tyrosine kinase receptor is a type of a cell membrane protein that is a member of a large group of receptor tyrosine kinases (RTKs). It is a neuronal receptor tyrosine kinase, which plays a role in the genesis and differentiation of the central nervous system [citation].
ALK tyrosine kinase acts as an enzyme that can accelerate biochemical reactions in cells. Generally, kinases are a specific type of enzyme that drives phosphorylation reactions on substrate proteins. Phosphorylation plays a critical role in regulating cellular processes such as cell cycle, growth, apoptosis, and signal transduction [citation].
How is ALK activated?
Although the exact mechanism is not yet completely understood, ALK tyrosine kinase is activated by cell surface ligand binding.
After activation, it transmits a signal to several downstream signaling pathways such as [citation]:
The RAS/MAPK pathway
the JAK/STAT pathway
the PI3K/Akt pathway, and
the PLC (phospholipase C)-γ pathway.
Mutations in the ALK gene can lead to changes in the protein that they encode which further leads to that given protein to change its function in different ways by being more or less active or inactive. These changes in protein function further lead to cause or can be associated with specific conditions and diseases.
What causes mutations in the ALK gene? What is the most common mutation in the ALK gene?
Most prominent of these mutations are gene rearrangement mutations, resulting in fusion genes (where two genes fuse, altering their original functions). The most frequent one of these fusion genes is the EML4-ALK fusion oncogene. Oncogenes are genes that cause cancer development by acquiring mutations in cancer cells which allow their survival and multiplication through different molecular mechanisms. Other gene partners that can fuse with the ALK gene are KIF5B, KLC1, TPR, HIP1, DCTN1, SQSTM1, NPM1, BCL11A, y BIRC6 [citation].
What does ALK mean in medical terms?
In the case of the ALK gene, mutations of the gene are primarily associated with NSCLC (non-small cell lung carcinoma). Apart from fusion genes, other mutations of the ALK gene also exist. For example, increased copy number (amplification of the gene) and activating point mutations (mutation of a single base pair of DNA) that result in kinase activation are also linked to the oncogenic activity of ALK [citation].
Does everyone have the ALK gene? Is the ALK gene hereditary?
All humans have the ALK gene, expressed in various tissues, where you obtain one copy from the mother and one from the father. Mutation in either copy of the gene can increase cancer risk [citation].
Most notably, mutations in the ALK gene contribute to the emergence of different cancers: lymphomas, neuroblastoma, and non-small cell lung cancer (NSCLC), to name a few [citation].
Mutations of this gene can be hereditary if they occur in germline cells (sex cells, sperm, and egg). However, this is far less common and has been chiefly described in some instances of neuroblastoma [citation]. The most common are mutations in the somatic cells (all other cells of our body), which can occur throughout a lifetime. [citation]. If you want to learn more about genetic mutations and different between somatic and germline mutations check out my blog post on this topic.
How do you identify an ALK mutation?
The existence of either ALK gene mutation can be tested by molecular methods such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and polymerase chain reaction-based techniques (PCR) but also next-generation genome sequencing and liquid biopsy (analysis of small fragments of DNA circulating in the blood).
Anyone can be tested for ALK mutations, but most importantly, tests are performed in people diagnosed with cancer and those who will start with cancer therapy. Biopsy samples are acquired and sent for analysis. Currently, cancer therapies are determined according to a rather personalized approach and according to many parameters, such as the age of the patient, type and spreading of the disease, stage of the disease, response to prior therapy, but also type of genetic mutation(s) which exist in a given cancer. Currently, cancers that harbor ALK gene mutations are best treated with targeted therapies, which aim to specifically impact only the protein which is behaving aberrantly or whose regulation is impacted in cancer - in this case, it is the ALK tyrosine kinase. These types of therapies aim to inhibit its aberrant action. [citation].
The challenge with ALK tyrosine kinase inhibitor therapies is the emergence of resistance to treatment through various underlying molecular mechanisms. In a nutshell - cancer cells devise mechanisms for therapy evasion by promoting their survival, usually by acquiring novel mutations, which enable their better adaptation and survival through a process called tumor evolution.
For this reason, other therapy approaches need to be applied, such as immunotherapy, which works by targeting cancer cells for destruction by the immune system, or chemotherapy and radiation.
Combination approaches are also used. For this reason, patients need to be tested multiple times to determine the types of mutations they have and mutations that are arising through the course of the disease, which confer therapy ineffectiveness or resistance. Patients can have one or more of these mutations.
What is Anaplastic large cell lymphoma (ALCL)
Anaplastic large cell lymphoma (ALCL) is a type of T-cell lymphoma – or non-Hodgkin lymphoma, which is relatively rare and develops from white blood cells called T cells [citation]. These types of lymphomas are genetically and morphologically heterogeneous and can be positive or negative for the ALK mutation. [citation]. The most common mutation is NPM-ALK t(2;5) translocation. The treatment approach is different for the two types [citation].
What does ALK mutation positive mean?
It means that an ALK mutation was detected in the sample. Positive ALK ALCL is treated with standard polychemotherapy regimens (more chemotherapy agents combined). In the first line of treatment, good results have been achieved with anthracycline-based chemotherapy regimens, including CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone), and CHOP-like protocols, CHOEP or MACOP-B [citation]. Other therapies are radiotherapy, stem cell transplants, and steroid therapy. ALCL ALK-negative cancer has a worse prognosis and usually occurs in older patients. These types of cancers are negative for the hallmark ALK rearrangement mutations. They can harbor a significant number of heterogeneous mutations, which are harder to map and even harder to target. It can also be treated with anthracycline-based chemotherapy regimens in the first line, but due to evident and common relapse, other therapies are needed [citation].
Etoposide is one drug that is frequently used. Usually, these types of cancers will need an autologous stem cell transplant (stem cells transplanted from oneself). Non-small cell lung cancers can be positive or negative for the ALK mutation. From all ALK mutations, ALK rearrangements, most notably EML4-ALK, are responsible for 3-7% of NSCLCs [citation]. ALK-positive cancers are treated with ALK inhibitors: Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib. After the development of therapy resistance, other treatments can be started, such as pemetrexed-based chemotherapy and radiation [citation].
What does ALK-negative mutation mean?
ALK-negative NSCLC represents cancer that does not harbor the ALK mutation but can have mutations in several other genes, such as KRAS, EGFR, MET, and others. In addition, the EGFR, ROS1, BRAF, NTRK, MET, and RET genes have mutations targetable with tyrosine kinase inhibitors. After developing resistance, patients are usually started on classic chemotherapy [citation] [citation].
Is it better to be ALK-positive or negative?
The ALCL survival rates are lower in the ALK-negative cases than in ALK-positive cases. Further survival rates depend on subsets of other mutations found in ALK-negative cases [citation] [citation].
For NSCLC, slightly better overall survival rates were lower for ALK-positive cases than ALK-negative cases. However, these results should be treated with care as survival rates further depend on subsets of other mutations specific for the ALK-positive cases and other parameters such as age, type of tumor, etc. [citation].
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