Thursday 19 June 2003
ALK rearrangements - ALK fusion
Chromosomal rearrangements involving the anaplastic lymphoma kinase gene (ALK) at 2p23 result in fusion with various partner genes leading to aberrant production of oncogenic protein products in multiple tumor types.
In tumorigenesis, the ALK gene at 2p23 is known to be fused to NPM, TPM3, TPM4, TFG, ATIC, CLTC, MSN, and ALO17.
ALK-ATIC by inv(2)(p23q35) in IMF (12939746)
ALK-TPM3 by t(1;2)(q25;p23)in IMF (MIM.191030)
ALK-RANBP2 (2q13) : Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor (12661011) at 2q11-q13 by t(2;2)(p23;q13)
ALK-TFG (TRK-fused gene) by t(2;3)(p23;q21) in ALCL (10556217)
ALK-SEC31L1 fusion gene by t(2;4)(p23;q21) in inflammatory myofibroblastic tumor (16161041)
ALK-NPM1 by t(2;5)(p23;q35) in ALCL
ALK-CARS by t(2;11;2)(p23;p15;q31) in IMT (12112524)
ALK-CLTC by t(2;17)(p23;q23): ALK/CLTC fusion gene (involving the clathrin gene CLTC at 17q23) in anaplastic large-cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL) and inflammatory myofibroblastic tumor (IMF) (11485898)
ALK-ALO17 by t(2;17)(p23;q25)in ALCL (12112524)
ALK-TPM4 by t(2;19)(p23;p13)in IMF
ALK-MYH9 by t(2;22)(p23;q11.2) (MYH9 at 22q11.2) in anaplastic large cell lymphoma (12800156)
ALK-MSN (moesin) by t(2;X)(p23;q11) in ALCL
ALK-EML4 fusion gene in non-small-cell lung cancer (6.7% of NSCLC) (17625570)
ALK-unknown gene by t(1;2)(q21; p23) (16831032)
ELM4-ALK fusion transcript in lung cancer or NSCLC
- The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature. Not all patients with lung cancer or NSCLC carry the ELM4-ALK fusion.
- Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or mutations in the KRAS gene.
- Approximately 4% of the 220,000 Americans diagnosed with lung cancer each year have the ALK fusion gene, and 45,000 newly diagnosed NSCLC patients are ALK positive worldwide.
- See ELM4-ALK lung cancer
ALK alterations in other tumors
Crizotinib (also known as PF-02341066 or 1066), is one of ALK-inhibitors, developed by Pfizer. It is currently undergoing clinical trials for its potential to treat advanced non-small cell lung carcinoma (NSCLC), a type of lung cancer.
Crizotinib is an oral ALK (anaplastic lymphoma kinase) inhibitor under study in patients with advanced NSCLC carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene.
The protein product of this fusion has constitutive kinase activity that is carcinogenic. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.
Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008 Jan;8(1):11-23. PMID: 18097461
Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions. Yeh I, de la Fouchardiere A, Pissaloux D, Mully TW, Garrido MC, Vemula SS, Busam KJ, LeBoit PE, McCalmont TH, Bastian BC. Am J Surg Pathol. 2015 Jan 19. PMID: 25602801
ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC. Mod Pathol. 2012 Jun 29. PMID: 22743654
Janoueix-Lerosey I, Lequin D, Brugières L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, Lyonnet S, Amiel J, Delattre O. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008 Oct 16;455(7215):967-70. PMID: 18923523
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara SI, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007 Jul 11; PMID: 17625570
Hirsch MS, Dal Cin P, Fletcher CD. ALK expression in pseudosarcomatous myofibroblastic proliferations of the genitourinary tract. Histopathology. 2006 Apr;48(5):569-78. PMID: 16623783
Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW. The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci. 2004 Dec;61(23):2939-53. PMID: 15583856
Cook JR, Dehner LP, Collins MH, Ma Z, Morris SW, Coffin CM, Hill DA. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol. 2001 Nov;25(11):1364-71. PMID: 11684952