Lung Cancer, ALK, G1269A

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Expand Collapse Lung Cancer  - General Description This year about 226,000 people in the U.S. will be told by a doctor that they have lung cancer. However, about 390,000 Americans remain alive today after having been diagnosed with this malignancy. Lung cancer includes tumors that begin in tissues lining air passages inside the lungs and bronchi. The bronchi are the 2 branches of the windpipe (trachea) that lead to the lungs. Based on how the cells look under a microscope, lung cancers are divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of these cases.

The main subtypes of NSCLC are squamous cell carcinoma (cancer beginning in thin, flat scaly-looking cells), adenocarcinoma (cancer beginning in cells that make mucus and other substances) and large cell carcinoma (cancer beginning in several types of large cells). The 2 main types of SCLC are small cell carcinoma (oat cell cancer) and combined small cell carcinoma.

Lung cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main sites to which lung cancer spreads are the adrenal gland, liver and lungs.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include MRI, bone scans and endoscopic ultrasound (EUS).

The FDA has approved several targeted therapies to treat patients with NSCLC. These include bevacizumab (Avastin), cetuximab (Erbitux), erlotinib (Tarceva), gefitnib (Iressa) and crizotinib (Xalkori). So far there are no FDA-approved targeted therapies for SCLC.

Despite significant improvements in the treatment of lung cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2012:

New cases: 226,160
Deaths: 160,340

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional and distant stage disease, respectively.

NSCLC arises from the epithelial cells of the lung, from the central bronchi to the terminal alveoli. The histological type of NSCLC correlates with the site of origin, reflecting the variation in respiratory tract epithelium from the bronchi to the alveoli. Squamous cell carcinoma usually starts near a central bronchus while adenocarcinoma usually originates in peripheral lung tissue.

Tobacco smoking is the strongest risk factor for developing lung cancer, though it should be noted that the majority of patients diagnosed with lung cancer quit smoking years prior to diagnosis or were never-smokers (up to 15% of cases).

The identification of driver oncogene mutations in lung cancer has led to the development of targeted therapy that has vastly broadened treatment options and improved outcomes for subsets of patients with metastatic disease. It is now common practice to determine the genotype of a NSCLC patient early in the course of their diagnosis, to ensure that all possible treatment options are considered.

Source: National Cancer Institute, 2012
This year about 226,000 people in the U.S. will be told by a doctor that they have lung cancer. However, about 390,000 Americans remain alive today after having been diagnosed with this malignancy. Lung cancer includes tumors that begin in tissues lining air passages inside the lungs and bronchi. The bronchi are the 2 branches of the windpipe (trachea) that lead to the lungs. Based on how the cells look under a microscope, lung cancers are divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of these cases.

The main subtypes of NSCLC are squamous cell carcinoma (cancer beginning in thin, flat scaly-looking cells), adenocarcinoma (cancer beginning in cells that make mucus and other substances) and large cell carcinoma (cancer beginning in several types of large cells). The 2 main types of SCLC are small cell carcinoma (oat cell cancer) and combined small cell carcinoma.

Lung cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main sites to which lung cancer spreads are the adrenal gland, liver and lungs.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include MRI, bone scans and endoscopic ultrasound (EUS).

The FDA has approved several targeted therapies to treat patients with NSCLC. These include bevacizumab (Avastin), cetuximab (Erbitux), erlotinib (Tarceva), gefitnib (Iressa) and crizotinib (Xalkori). So far there are no FDA-approved targeted therapies for SCLC.

Despite significant improvements in the treatment of lung cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2012:

New cases: 226,160
Deaths: 160,340

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional and distant stage disease, respectively.

NSCLC arises from the epithelial cells of the lung, from the central bronchi to the terminal alveoli. The histological type of NSCLC correlates with the site of origin, reflecting the variation in respiratory tract epithelium from the bronchi to the alveoli. Squamous cell carcinoma usually starts near a central bronchus while adenocarcinoma usually originates in peripheral lung tissue.

Tobacco smoking is the strongest risk factor for developing lung cancer, though it should be noted that the majority of patients diagnosed with lung cancer quit smoking years prior to diagnosis or were never-smokers (up to 15% of cases).

The identification of driver oncogene mutations in lung cancer has led to the development of targeted therapy that has vastly broadened treatment options and improved outcomes for subsets of patients with metastatic disease. It is now common practice to determine the genotype of a NSCLC patient early in the course of their diagnosis, to ensure that all possible treatment options are considered.

Source: National Cancer Institute, 2012
Expand Collapse ALK  - General Description
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The ALK gene (ALK stands for Anaplastic Lymphoma Kinase) encodes a protein that is located on the cell surface and belongs to a family of receptor tyrosine kinases (RTKs). RTKs are the first link in a chain that sends signals from the outside of a cell to the signal cascades inside the cell that control different cellular processes, such as cell growth, cell division and cell differentiation.

ALK is believed to play a role in brain development and helps to regulate the proliferation of nerve cells during early stages of development. In several types of cancer, the ALK gene has been found to be genetically altered, and these alterations result in abnormal ALK proteins that cannot be normally regulated by the cell.

Many types of genetic alterations in the ALK gene have been found in different cancers. Some cancers contain ALK genes that have genetic mutations, or changes in the nucleotide sequence in the ALK gene. Other types of cancers have been found to have amplified ALK, meaning that many copies of the ALK gene have been added to the DNA. This leads to a higher level of the ALK protein in tumor cells, overwhelming the cells normal ability to regulate the ALK protein. Another type of genetic alteration in the ALK gene that is found in cancer is called gene fusions or gene rearrangements. This is the result of an event where a portion of the ALK gene breaks away from its normal location on the DNA, and inserts itself into a different gene in another location. The protein that results from this event is a fusion protein-part ALK, and part of another protein. The gene-fusions found in cancer are activated, and like the mutations and amplifications described above, send continual signals to the cell to grow and divide, resulting in cancer.

Source: Genetics Home Reference
ALK is a gene that provides the code for making a protein called anaplastic lymphoma kinase. This protein belongs to a family of proteins on the cell surface known as receptor tyrosine kinases (RTKs). RTKs are the first link in a chain that sends signals from the outside of a cell to the parts inside the cell that control different cellular processes, such as cell growth, cell division and cell differentiation. Anaplastic lymphoma kinase is believed to play a key role in brain development and helps regulate the proliferation of nerve cells during early stages of development. In cancer, either due to mutation or rearrangements in the ALK gene, its activity is continuously switched on, which in turn drives the cancer process.

At least 16 mutations in the ALK gene have been found in some patients with neuroblastoma, a cancer that develops in the immature nerve cells (neuroblasts) during childhood. In most cases, each mutation alters the structure of the ALK protein in different ways. These mutations result in the signaling pathway being switched on, increasing the proliferation of immature nerve cells and leading to neuroblastoma. Some of these mutations are inherited and some are called somatic because they are acquired during the course of a person's life and are found only in cells that become cancerous (not inherited from a parent). In some people with neuroblastoma, extra copies (gene amplification) of ALK cause too much protein to be made.

Rearrangements in the ALK gene also serve as an important driver of tumor growth. These rearrangements result in the production of a recombinant protein that is comprised of the front end of one protein fused together with the tyrosine kinase domain of ALK. The fusion partner can be any one of a number of genes, depending on the malignancy. For instance, in approximately 70 to 80% of ALK-positive anaplastic large cell lymphomas (ALCL), ALK is paired with the Nucleophosmin (NPM) gene. In lung cancer, ALK's translocation partner is primarily the EML4 gene. ALK rearrangements have also been described in other tumors including inflammatory myofibroblastic tumors, neural tumors, rhabdomyosarcomas and in some subtypes of breast cancer. Another type of rearrangement, an inversion, is found in a few people with non-small cell lung cancer (NSCLC), the most common type of lung cancer.

Source: Genetics Home Reference
Expand Collapse G1269A  in ALK
The ALK mutation G1269A indicates a fusion between the EML4 gene and the ALK gene, which produces an oncogenic fusion-protein.
The ALK mutation G1269A indicates a fusion between the EML4 gene and the ALK gene, which produces an oncogenic fusion-protein.

A frequent genetic alteration in the ALK gene found in lung cancers is called a gene rearrangement. In this type of mutation, a portion of the ALK gene has moved from the position in the DNA where it is normally found to a different gene in another location in the DNA. ALK translocations often involve the EML4 gene. When translocated, the result is a fusion protein that is part ALK and part EML4. This fusion protein is active, sending signals to cancer cells to grow and divide. The fusion G1269A is one of the fusion proteins found in lung cancers.

Novel therapeutic strategies to treat ALK fusion proteins have been developed. Mutations such as G1269A may be indications for a specific treatment recommendation by an oncologist.

Testing for genetic alterations in the ALK gene is performed in the MGH Center for Integrated Diagnostics. Treatment for ALK-mutated lung cancers is available at the MGH Cancer Center, as are clinical trials testing the newest and most promising therapies to improve patient outcomes.


A frequent genetic alteration in the ALK gene found in lung cancers is called a gene rearrangement. In this type of mutation, a portion of the ALK gene has moved from the position in the DNA where it is normally found to a different gene in another location in the DNA. ALK translocations often involve the EML4 gene. When translocated, the result is a fusion protein that is part ALK and part EML4. This fusion protein is active, sending signals to cancer cells to grow and divide. The fusion G1269A is one of the fusion proteins found in lung cancers.

Novel therapeutic strategies to treat ALK fusion proteins have been developed. Mutations such as G1269A may be indications for a specific treatment recommendation by an oncologist.

Testing for genetic alterations in the ALK gene is performed in the MGH Center for Integrated Diagnostics. Treatment for ALK-mutated lung cancers is available at the MGH Cancer Center, as are clinical trials testing the newest and most promising therapies to improve patient outcomes.


Our Lung Cancer Team

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 85 Per Page:
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Protocol # Title Location Status Match
NCT02817633 A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors MGH Open DG
NCT03202940 A Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC A Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC MGH Open DG
NCT02927340 A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions MGH Open DG
NCT03052608 A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC A Study Of Lorlatinib Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC MGH Open DG
NCT00585195 A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer MGH Open DG
NCT03093116 A Study of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements A Study of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements MGH Open DG
NCT02568267 Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) MGH Open DG
NCT02201992 Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment Trial) Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment Trial) MGH Open DG
NCT02193282 Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial) Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial) MGH Open DG
NCT03178071 Expanded Access For Lorlatinib For Patients With Non Small Cell Lung Cancer ALK Positive or ROS1 Positive Expanded Access For Lorlatinib For Patients With Non Small Cell Lung Cancer ALK Positive or ROS1 Positive MGH Open DG
Trial Status: Showing Results: 1-10 of 85 Per Page:
123456789Next »
Our Lung Cancer Team

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