ALK; anaplastic lymphoma receptor tyrosine kinase (2p23)

Gene Summary

Gene:ALK; anaplastic lymphoma receptor tyrosine kinase
Aliases: CD246, NBLST3
Summary:This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:ALK tyrosine kinase receptor
Updated:14 December, 2014


What does this gene/protein do?
Show (15)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (9)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lung CancerALK and Lung Cancer View Publications493
Lung Cancer, Non-Small CellALK and Non-Small Cell Lung Cancer View Publications306
Lung Cancer, Non-Small CellALK-EML4 Rearrangements in NSCLC View Publications207
Non-Hodgkin Lymphomat(2;5)(p23;q35) NPM1-ALK translocation in Anaplastic large cell lymphoma View Publications168
NeuroblastomaALK and Neuroblastoma View Publications85
Neuroblastoma, Familial ALK mutations in Familial Neuroblastoma View Publications15
Non-Hodgkin LymphomaATIC-ALK Rearrangements in anaplastic large cell lymphoma View Publications3
-ALK-RANBP2 Rearrangements in Inflammatory Myofibroblastic Tumor View Publications2
Non-Hodgkin LymphomaALK-CTCL Rearrangements in diffuse large B-cell lymphoma View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: ALK (cancer-related)

Lovly CM, McDonald NT, Chen H, et al.
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Nat Med. 2014; 20(9):1027-34 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

Related: Lung Cancer IGF1R Crizotinib (Xalkori)

Teoh JY, Chan NH, Cheung HY, et al.
Inflammatory myofibroblastic tumors of the urinary bladder: a systematic review.
Urology. 2014; 84(3):503-8 [PubMed] Related Publications
We systemically reviewed the literature on inflammatory myofibroblastic tumors (IMTs) of the urinary bladder and compared between anaplastic lymphoma kinase (ALK)-positive and ALK-negative IMTs. An extensive search of the literature was performed in Medline and Web of Science using the following terms: "inflammatory myofibrolastic tumor," "inflammatory pseudotumor," and "bladder." A manual search was also performed using the web-based search engine Google Scholar. Reference lists of the retrieved articles were reviewed for other relevant studies. Patients' and disease characteristics of each individual case were reviewed. Further analyses were performed to compare between ALK-positive and ALK-negative IMTs. Forty-one studies were identified, and 182 patients were included for review and subsequent analyses. Of the IMTs, 65% were ALK-positive. Local tumor recurrence rate was 4%, and no cases of distant metastases have been reported. Compared with ALK-negative IMTs, ALK-positive IMTs had a female predilection with a sex ratio (male:female) of 1:1.67 (P = .048). ALK-positive IMTs also appeared to occur in younger patients (P = .072). No significant differences were noted in terms of their clinical presentations and histologic features. On immunohistochemical staining, ALK-positive IMTs had more positive results for desmin (P = .042) and p53 (P = .05), and more negative results for clusterin (P = .003). In summary, ALK-positive IMTs of the urinary bladder had a female predilection, appeared to occur more frequently in younger patients, and had different immunohistochemical staining patterns when compared with ALK-negative IMTs. Regardless of its ALK status, IMT of the urinary bladder has a good prognosis after surgical resection.

Related: Bladder Cancer Bladder Cancer - Molecular Biology

Vijayvergia N, Mehra R
Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer.
Cancer Chemother Pharmacol. 2014; 74(3):437-46 [PubMed] Related Publications
The revolution in individualized therapy for patients with advanced non-small cell lung cancer (NSCLC) has seen the emergence of a number of molecularly targeted therapies for distinct patient molecular subgroups. Activating anaplastic lymphoma kinase (ALK)-gene rearrangement has been detected in 3-7 % of NSCLC cases, and the ALK inhibitor crizotinib is now an approved treatment for patients with tumors harboring this event. However, resistance to ALK-targeted therapies is a ubiquitous problem in the management of advanced ALK-positive NSCLC and can be mediated by secondary kinase mutations or the activation of compensatory alternative oncogenic drivers. New, more potent ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802), and AP26113 are now emerging, together with an increased knowledge of the molecular basis of resistance. There is a need to evaluate the optimal clinical application of these new agents, either as sequential therapies or in combination with other targeted agents, to combat resistance and prolong survival in patients with ALK-positive NSCLC. The remarkable clinical activity of ALK inhibitors also emphasizes the importance of optimal diagnostic testing algorithms, to ensure that all eligible patients receive these breakthrough therapies.

Related: Non-Small Cell Lung Cancer Lung Cancer Crizotinib (Xalkori)

Schleiermacher G, Janoueix-Lerosey I, Delattre O
Recent insights into the biology of neuroblastoma.
Int J Cancer. 2014; 135(10):2249-61 [PubMed] Related Publications
Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genome-wide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.

Related: Neuroblastoma

Lee HJ, Zhuang G, Cao Y, et al.
Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.
Cancer Cell. 2014; 26(2):207-21 [PubMed] Related Publications
Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.

Related: Lung Cancer Signal Transduction KRAS gene EGFR Erlotinib (Tarceva)

Hiraoka M
[Companion diagnostics with FISH assay (HER2, ALK)].
Rinsho Byori. 2014; 62(4):390-8 [PubMed] Related Publications
In recent anti-cancer drug treatment, personalized medicine has become popular with the development of many molecularly-targeted drugs. Companion Diagnostics (CDx) identify and detect biomarkers to predict whether a drug will work or have adverse effects on patients. We developed two CDx with FISH assays, the PathVysion HER-2 DNA Probe Kit and Vysis ALK Break Apart FISH Probe Kit. The PathVysion HER-2 DNA Probe Kit is a test to detect amplification of the HER2 gene in tissue samples from breast cancer patients to aid in determining and identifying patients eligible for treatment with Trastuzumab. The Vysis ALK Break Apart FISH Probe Kit is a test to detect rearrangements involving the ALK gene in tissue samples from non-small cell lung cancer (NSCLC) patients to aid in identifying patients eligible for treatment with Crizotinib. In this article, we review the CDx, focusing on HER2 gene and ALK fusion testing.

Related: Breast Cancer Non-Small Cell Lung Cancer FISH

Fukutsuka K, Takubo T
[Companion diagnostics in the era of personalized medicine--chairmen's introductory remarks].
Rinsho Byori. 2014; 62(4):378-80 [PubMed] Related Publications
Personalized medicine is a medical model that proposes the customization of treatment for individual patients. In this model, diagnostic tests are essential for selecting safer and more efficacious treatments. The term "companion diagnostics" has been used to describe these tests, whereby molecular assays that measure the levels of proteins or specific gene mutations are used to provide a specific therapy for an individual by stratifying the disease status, selecting the proper medication, and tailoring dosages. Examples of companion diagnostics in the field of cancer medicine for molecular targeted therapy include tests for the ALK-fusion gene in non-small cell lung cancer and expression of CCR4 in adult T-cell leukemia. For breast cancer, the expression of HER2 protein is evaluated by immunohistochemistry (IHC), and gene amplification of HER2 is tested by fluorescence in situ hybridization (FISH); both tests consist of pre-analysis, analysis, and post-analysis processes that require quality control to ensure the reliability of the results. This symposium includes: 1) future aspects of companion diagnostics addressing many of the problems that must be overcome, 2) companion diagnostics using FISH focusing on HER2 amplification and ALK alteration, 3) newly developed diagnostic tests using tumor specimens and cell-free DNA in serum, and 4) CCR4 expression detected by IHC and flow cytometry.

Related: Breast Cancer Non-Small Cell Lung Cancer FISH

Ormanns S, Assmann G, Reu S, et al.
ALK expression is absent in pancreatic ductal adenocarcinoma.
J Cancer Res Clin Oncol. 2014; 140(9):1625-8 [PubMed] Related Publications
PURPOSE: It has not yet been clearly defined whether anaplastic lymphoma kinase (ALK) expression can be detected in pancreatic ductal adenocarcinoma (PDAC).
METHODS: Within a retrospective study, archival PDAC surgical specimens were screened for ALK expression in tumor and normal tissue by immunohistochemistry (IHC) with the use of a specific ALK detection kit on a tissue microarray (TMA).
RESULTS: PDAC tumor tissue was available from 99 resected cases: fifty-eight out of 99 patients (59 %) had nodal-positive disease, and 80 patients (81 %) had pT3 tumors. Forty-nine patients underwent R0 resection, and in 48 cases, resection status was classified R1. Regarding ALK expression, five cases showed faint immunoreactivity on TMA, which was negative on whole mount sections. All other 94 cases showed no ALK expression.
CONCLUSION: In 99 PDAC cases, no ALK expression was detected by IHC; ALK thus may not serve as a relevant drug target in PDAC.

Related: Cancer of the Pancreas Pancreatic Cancer

Iwama E, Takayama K, Baba E, Nakanishi Y
[Personalized medicine in non-small-cell carcinoma].
Fukuoka Igaku Zasshi. 2014; 105(3):57-66 [PubMed] Related Publications

Ryslik GA, Cheng Y, Cheung KH, et al.
A spatial simulation approach to account for protein structure when identifying non-random somatic mutations.
BMC Bioinformatics. 2014; 15:231 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Current research suggests that a small set of "driver" mutations are responsible for tumorigenesis while a larger body of "passenger" mutations occur in the tumor but do not progress the disease. Due to recent pharmacological successes in treating cancers caused by driver mutations, a variety of methodologies that attempt to identify such mutations have been developed. Based on the hypothesis that driver mutations tend to cluster in key regions of the protein, the development of cluster identification algorithms has become critical.
RESULTS: We have developed a novel methodology, SpacePAC (Spatial Protein Amino acid Clustering), that identifies mutational clustering by considering the protein tertiary structure directly in 3D space. By combining the mutational data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and the spatial information in the Protein Data Bank (PDB), SpacePAC is able to identify novel mutation clusters in many proteins such as FGFR3 and CHRM2. In addition, SpacePAC is better able to localize the most significant mutational hotspots as demonstrated in the cases of BRAF and ALK. The R package is available on Bioconductor at: http://www.bioconductor.org/packages/release/bioc/html/SpacePAC.html.
CONCLUSION: SpacePAC adds a valuable tool to the identification of mutational clusters while considering protein tertiary structure.

Related: Cancer Prevention and Risk Reduction

Morodomi Y, Takenoyama M, Inamasu E, et al.
Non-small cell lung cancer patients with EML4-ALK fusion gene are insensitive to cytotoxic chemotherapy.
Anticancer Res. 2014; 34(7):3825-30 [PubMed] Related Publications
BACKGROUND: Although patients with the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene (EML4-ALK) re-arrangement and epidermal growth factor gene EGFR mutations have proven sensitive to specific inhibitors, there is currently no consensus regarding the sensitivity of non-small cell lung cancer (NSCLC) patients with such mutations to cytotoxic chemotherapy.
PATIENTS AND METHODS: The responses to first-line cytotoxic chemotherapy were retrospectively compared between advanced or postoperative recurrent patients with non-squamous NSCLC who harbor the EML4-ALK fusion gene (ALK+), EGFR mutation (EGFR+), or neither abnormality (wild-type).
RESULTS: Data for 22 ALK+, 30 EGFR+, and 60 wild-type patients were analyzed. The ALK+ group had a significantly lower response rate than the other two groups. Progression-free survival was significantly shorter in the ALK+ cohort compared to the EGFR+ (p<0.001) and wild-type cohorts (p=0.0121).
CONCLUSION: NSCLC patients with the EML4-ALK fusion gene might be relatively insensitivite to cytotoxic chemotherapy.

Related: Non-Small Cell Lung Cancer Lung Cancer EGFR

Homa I, Sawicki M, Wojas-Krawczyk K, et al.
Rare co-existence of mutation in KRAS and ALK gene re-arrangement in an adenocarcinoma patient--a case report.
Anticancer Res. 2014; 34(7):3701-5 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK) gene re-arrangements are present in approximately 4% of patients with non-small cell lung cancer (NSCLC), mostly in non-smokers with adenocarcinoma. V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are more common in smokers. These molecular lesions were usually described as are mutually exclusive. We herein describe a rare case of co-existence of ALK and KRAS abnormalities in adenocarcinoma tumor with massive local growth (disproportionality of clinical symptoms) and rapid central nervous system (CNS) metastases spread. T3N1M0 stage tumor (size: 10×12×13 cm) in upper lobe of the right lung was diagnosed in a 56-year-old Caucasian male smoker. Adenocarcinoma of solid predominant was surgically resected with chest wall reconstruction. One month after surgery, CNS metastases were diagnosed and subsequently treated with radiotherapy. We noted an 8-month overall survival from tumor resection. In the case of comorbidity of disorders in the ALK (uncertain prognostic significance) and KRAS gene (described as unfavorable prognostic factor), these abnormalities may ultimately decide the course of the disease in the form of brain metastases.

Related: Lung Cancer KRAS gene

Gilani SM, Kowalski PJ
Inflammatory myofibroblastic tumour: a rare entity with wide differential diagnosis.
Pathologica. 2014; 106(1):1-6 [PubMed] Related Publications
Inflammatory myofibroblastic tumour (IMT) is a rare, distinctive mesenchymal neoplasm. Grossly, it appears as a circumscribed mass with a rubbery to firm cut surface. Microscopically, it is characterized by a spindle cell proliferation within a myxoid stroma with admixed plasma cells, lymphocytes and eosinophils. Immunohistochemical staining is usually positive for vimentin, smooth muscle actin (SMA) and anaplastic lymphoma kinase (ALK). ALK gene rearrangement is present in approximately 50-70% IMTs. The standard treatment is surgical resection, and it is essential to differentiate IMT from benign and malignant mimickers so that appropriate therapy may be provided. Clinical and radiological follow-up is required to detect recurrence.

Kim TJ, Park CK, Yeo CD, et al.
Simultaneous diagnostic platform of genotyping EGFR, KRAS, and ALK in 510 Korean patients with non-small-cell lung cancer highlights significantly higher ALK rearrangement rate in advanced stage.
J Surg Oncol. 2014; 110(3):245-51 [PubMed] Related Publications
BACKGROUND: Simultaneous genotyping has advantages in turnaround time and detecting the real mutational prevalence in unresectable non-small-cell lung cancer (NSCLC), a group not previously genetically characterized.
METHODS: We developed simultaneous panel of screening EGFR and KRAS mutations by direct sequencing or PNA clamping, and ALK rearrangement by fluorescent in situ hybridization (FISH) in multicenter manner.
RESULTS: Of 510 NSCLC Korean patients, simultaneous genotyping identified mutations of EGFR (29.0%) and KRAS (8.6%) and rearrangement of ALK (9.2%). Seven patients had overlaps in mutations. Although several well-known associations between genotypes and clinical characteristics were identified, we found no relationship between ALK rearrangement and sex or smoking history. Unlike the other genotype mutations, ALK rearrangement was associated with advanced disease. Among the ALK-negative group, patients with 10-15% of ALK FISH split shared characteristics, such as younger age and advanced stage disease, more with the ALK-positive group (>15% ALK FISH split) than <10% ALK FISH split group.
CONCLUSIONS: Simultaneous panel genotyping revealed more prevalent ALK rearrangements than reported in previous studies and their strong association with advanced stage irrespective of sex or smoking history. ALK rearrangement seems to be a marker for aggressive tumor biology and should be assessed in advanced disease.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer KRAS gene EGFR

Xu J, Wei S
Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity.
Arch Pathol Lab Med. 2014; 138(6):842-6 [PubMed] Related Publications
Primary breast anaplastic large cell lymphoma (ALCL) is rare but is more commonly seen in patients with implants; fewer than 50 cases of breast implant-associated ALCL have been reported in the English language literature. Breast implant-associated ALCL is not a disease of the breast parenchyma, but instead is a disease of the fibrous capsule surrounding the implant. The patients usually present with an effusion around the implant and, rarely, with a solid mass. Morphologically, the neoplastic cells are large, epithelioid, and pleomorphic, with abundant cytoplasm, vesicular irregular nuclei, and frequent mitoses. Occasional "hallmark" cells may be present. The lesional cells typically show strong and diffuse immunoreactivity for CD30 and often express T-cell markers, cytotoxic-associated antigens, and epithelial membrane antigen. Almost all reported cases are negative for anaplastic lymphoma kinase. Molecular genetic analyses have demonstrated T-cell receptor gene rearrangements. The differential diagnosis essentially includes poorly differentiated carcinoma, other lymphomas, and chronic inflammation. Once a diagnosis of lymphoma is established, it is important to exclude systemic anaplastic lymphoma kinase-negative ALCL involving the breast, primary cutaneous ALCL, and other CD30(+) lymphoproliferative disorders. The patients with effusion-associated ALCL often have an indolent course and excellent prognosis, responding well to excision of the fibrous capsule around the implant (capsulectomy) and implant removal. In contrast, patients who present with a distinct mass may have a more aggressive course and poor prognosis, requiring chemotherapy and/or radiation therapy.

Related: Breast Cancer

Demidova I, Barinov A, Savelov N, et al.
Immunohistochemistry, fluorescence in situ hybridization, and reverse transcription-polymerase chain reaction for the detection of anaplastic lymphoma kinase gene rearrangements in patients with non-small cell lung cancer: potential advantages and methodologic pitfalls.
Arch Pathol Lab Med. 2014; 138(6):794-802 [PubMed] Related Publications
CONTEXT: Echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion was shown to be the driver of tumorigenesis in approximately 3% to 5% of patients with non-small cell lung cancer (NSCLC) and is associated with response to inhibition with crizotinib. However, no complete agreement regarding the best diagnostic test for identification of ALK rearrangements has been achieved yet.
OBJECTIVE: To investigate the concordance, sensitivity, and specificity of immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription-polymerase chain reaction (RT-PCR) for detection of ALK rearrangements.
DESIGN: Thirty-six prospectively tested patients with NSCLC who had adenocarcinoma and 10 ALK-positive samples were included in the study. All samples were tested by IHC (ALK1 clone, 5A4 clone, D5F3 clone), FISH (LSI ALK Break Apart and ALK FISH Probe), and multiplexed RT-PCR.
RESULTS: Immunohistochemistry staining was successful in all samples.. Clone D5F3 showed the best sensitivity and specificity of 100%; clones ALK1 and 5A4 showed sensitivities of 91% with specificity of 100%. Both FISH probes showed concordance with sensitivity and specificity of 100%. Hybridization and RT-PCR were successful in 98% and 93.4% of samples, respectively, with sensitivity of 88% and specificity of 100%. Frequent artifacts leading to misinterpretation were observed with all 3 methodologies.
CONCLUSIONS: All 3 methodologies showed good sensitivity, specificity, and concordance, when artifacts were characterized and excluded. However, all ambiguous cases have to be confirmed as ALK rearranged by at least 2 of the 3 methods.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer

Tachihara M, Kobayashi K, Ishikawa Y, et al.
Successful crizotinib rechallenge after crizotinib-induced interstitial lung disease.
Jpn J Clin Oncol. 2014; 44(8):762-4 [PubMed] Related Publications
We report the case of a 70-year-old Japanese male diagnosed with advanced lung adenocarcinoma harboring the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. As soon as crizotinib was administered, tumor shrank immediately. On Day 25, he developed interstitial lung disease. Bronchoalveolar lavage fluid analysis demonstrated elevated lymphocytes fractionation. A drug lymphocyte stimulating test for crizotinib with the bronchoalveolar lavage lymphocytes was negative. Crizotinib administration was discontinued, but a life-threatening flare of tumor growth occurred. Since there was no alternative treatment for the lung cancer, we restarted crizotinib in combination with prednisolone. The patient experienced neither disease progression nor recurrence of interstitial lung disease at 6 months. In cases in which no alternate treatment is known, crizotinib retreatment combined with steroid therapy after crizotinib-induced interstitial lung disease could be considered after a careful consideration of the potential risks and benefits.

Related: Non-Small Cell Lung Cancer Lung Cancer Crizotinib (Xalkori)

Kris MG, Johnson BE, Berry LD, et al.
Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
JAMA. 2014; 311(19):1998-2006 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
IMPORTANCE: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES: To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS: From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS: Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES: Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS: From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE: Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01014286.

Related: Lung Cancer

Zer A, Leighl NB
Second-line therapy in non-small-cell lung cancer: the DELTA between different genotypes widens.
J Clin Oncol. 2014; 32(18):1874-81 [PubMed] Related Publications

Tomiyama A, Uekita T, Kamata R, et al.
Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association.
Cancer Res. 2014; 74(14):3790-801 [PubMed] Related Publications
Neuroblastomas harbor mutations in the nonreceptor anaplastic lymphoma kinase (ALK) in 8% to 9% of cases where they serve as oncogenic drivers. Strategies to reduce ALK activity offer clinical interest based on initial findings with ALK kinase inhibitors. In this study, we characterized phosphotyrosine-containing proteins associated with ALK to gain mechanistic insights in this setting. Flotillin-1 (FLOT1), a plasma membrane protein involved in endocytosis, was identified as a binding partner of ALK. RNAi-mediated attenuation of FLOT1 expression in neuroblastoma cells caused ALK dissociation from endosomes along with membrane accumulation of ALK, thereby triggering activation of ALK and downstream effector signals. These features enhanced the malignant properties of neuroblastoma cells in vitro and in vivo. Conversely, oncogenic ALK mutants showed less binding affinity to FLOT1 than wild-type ALK. Clinically, lower expression levels of FLOT1 were documented in highly malignant subgroups of human neuroblastoma specimens. Taken together, our findings suggest that attenuation of FLOT1-ALK binding drives malignant phenotypes of neuroblastoma by activating ALK signaling.

Related: Neuroblastoma Signal Transduction

Seo AN, Yang JM, Kim H, et al.
Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas.
Br J Cancer. 2014; 110(11):2688-99 [PubMed] Article available free on PMC after 27/05/2015 Related Publications
BACKGROUND: c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas.
METHODS: In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2.
RESULTS: We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS).
CONCLUSIONS: c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death.

Related: Chromosome 8 Lung Cancer KRAS gene EGFR

Rüping K, Altendorf-Hofmann A, Chen Y, et al.
High IGF2 and FGFR3 are associated with tumour progression in undifferentiated pleomorphic sarcomas, but EGFR and FGFR3 mutations are a rare event.
J Cancer Res Clin Oncol. 2014; 140(8):1315-22 [PubMed] Related Publications
AIM: Pleomorphic undifferentiated sarcomas (formerly known as malignant fibrous histiocytomas) are recognised by the actual WHO classification as an undifferentiated, unclassifiable category of pleomorphic sarcomas which show no definable line of differentiation and are still a diagnosis of exclusion. Therefore, diagnostic, prognostic and therapeutic options of these tumours are urgently needed.
METHODS: Three hundred and twenty-seven spindle cell tumours of a German consultation and reference centre of soft tissue tumours consisting of 200 undifferentiated pleomorphic sarcomas (UPS), 45 low-grade sarcomas (10 low-grade fibromyxoid sarcomas, 32 low-grade myofibroblastic sarcomas and three myxoinflammatory fibroblastic sarcomas) and 82 tumours of the fasciitis family were revisited. The specimens were analysed immunohistochemically with distinct markers including tyrosine kinases and expression correlated with clinicopathological parameters. Additionally, mutational analysis was performed on specimens with high expression of EGFR and FGFR3.
RESULTS: At the protein level high IGF2 expression was observed in 86 %, FGFR3 (69 %), PDGFRA (62 %), PDGFRB (39 %), FGFR1 (8 %), EGFR (5 %), KDR/VEGFR2 (3 %), ALK (0 %) and high Ki67 (63 %) in UPS. High expressions of IGF2 and FGFR3 are significantly correlated with a higher grading (p = 0.023 and p = 0.016, respectively) and a high Ki67 index (p = 0.017 and p = 0.001, respectively). No mutations were found in the hot spots of tumour specimens with a high expression of EGFR gene (exons 18-21) and FGFR3 gene (exons 7, 10 and 15).
CONCLUSIONS: High expressions of IGF2 and FGFR3 are significantly associated with tumour progression, grading and Ki67 and might classify a subgroup of undifferentiated pleomorphic sarcoma. These markers might guide targeted therapies in these neoplasms.

Related: IGF2 Soft Tissue Sarcomas EGFR

Varesano S, Leo C, Boccardo S, et al.
Status of Anaplastic Lymphoma Kinase (ALK) in malignant mesothelioma.
Anticancer Res. 2014; 34(5):2589-92 [PubMed] Related Publications
BACKGROUND: Malignant mesothelioma (MM) is a particularly aggressive type of primary tumor, associated with exposure to asbestos, and characterized by high mortality. To date, there is no curative therapy for MM. The receptor anaplastic lymphoma kinase (ALK) was found to be mutated in many cases of cancer and used as a target in biological therapies. We investigated whether this pharmacological treatment could also be applicable to MM.
MATERIALS AND METHODS: The state of ALK was analyzed by immunohistochemistry and fluorescent in situ hybridization in 63 MM tissue specimens.
RESULTS: None of the 63 MM samples showed overexpression or translocation of ALK.
CONCLUSION: Our preliminary data exclude the utility of analysis of the ALK gene in MM and suggest that ALK inhibitor therapy is not applicable to MM.

Related: FISH Lung Cancer Mesothelioma

Salmenkivi K, Knuuttila A
[Diagnostics of non-small cell lung carcinoma].
Duodecim. 2014; 130(7):701-4 [PubMed] Related Publications
ALK inhibitor therapy is individual cancer treatment, in which the targeted drug therapy is directed to a patient group that is likely to benefit from the therapy. The detection in the tumor of ALK gene (anaplastic lymphoma kinase) rearrangement is a prerequisite for the ALK inhibitor therapy for non-small cell lung carcinoma. The ALK assay should be performed for non-squamous cellular non-small cell lung carcinomas, especially adenocarcinomas. It is not recommended to be based on the patients' clinical features. The immunohistochemical method is well suited for screening of ALK positivity. The present recommendation is to ascertain the ALK gene rearrangement from immunopositive specimens by using the FISH procedure.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer

Guo L, Liu X, Qiu T, et al.
[ALK fusion gene assessment by fully automatic immunohistochemistry in non-small cell lung cancer].
Zhonghua Bing Li Xue Za Zhi. 2014; 43(2):95-8 [PubMed] Related Publications
OBJECTIVE: To evaluate the sensitivity and specificity of fully automated immunohistochemistry (IHC), with comparison to FISH, in the detection of EML4-ALK rearrangement in lung adenocarcinoma (ADC); and the use of IHC as a pre-screening tool.
METHODS: A total of 404 paraffin-embedded NSCLC samples from surgical resections were tested by IHC with Ventana anti-ALK rabbit monoclonal antibody (D5F3) and ultrasensitive detection kit. ALK rearrangement was further confirmed by FISH.
RESULTS: Twenty-nine of 404 lung ADCs (7.2%) were positive for ALK by IHC. ALK positive tumor cells demonstrated strong and diffused granular cytoplasmic staining. All the ALK IHC-positive cases were confirmed to harbor ALK rearrangement by FISH. None of the ALK IHC-negative cases was FISH-positive.
CONCLUSIONS: IHC can effectively detect ALK rearrangement in lung cancer. It may provide a reliable and cost-effective diagnostic approach in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer

Rafael OC, Aziz M, Raftopoulos H, et al.
Molecular testing in lung cancer: fine-needle aspiration specimen adequacy and test prioritization prior to the CAP/IASLC/AMP Molecular Testing Guideline publication.
Cancer Cytopathol. 2014; 122(6):454-8 [PubMed] Related Publications
BACKGROUND: Subtyping of lung carcinoma with immunohistochemistry is essential for diagnosis, whereas molecular testing (MT) is required for therapy guidance. In the current study, the authors report on MT performed on fine-needle aspiration specimens at the study institution over a 2-year period preceding the April 2013 College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) Molecular Testing Guideline (MTG) publication.
METHODS: The database of the study institution was retrospectively queried for cases of lung and thoracic/lower cervical lymph node fine-needle aspiration specimens for 2011 through 2012.
RESULTS: Of 246 selected cases, 26 featured a limited amount of material in cell blocks. MT increased significantly between 2011 and 2012 and was requested in 39.4% of cases (97 of 246 cases): 86 of those cases had at least 1 MT result and 11 had insufficient material for any MT. Anaplastic lymphoma kinase (ALK) testing was performed in 9 cases in which DNA was insufficient for epidermal growth factor receptor (EGFR) testing. In addition, 13 cases of adenocarcinoma/non-small cell lung carcinoma had at least 1 MT canceled because of insufficient DNA, but at the same time had an average of 3.46 immunohistochemical stains performed.
CONCLUSIONS: Of all the cytology specimens, 10.6% featured limited material; however, no universally accepted testing sequence priority was available at the time the study was performed. As per the MTG, MT should take precedence over immunohistochemistry in cases of adenocarcinoma/non-small cell lung carcinoma. Approximately 5.3% of the specimens in the current study had insufficient material for MT while having multiple stains performed instead. The MTG also recommend performing EGFR before ALK testing; the authors found 9 cases with insufficient material for EGFR testing that had ALK testing performed. The results of the current study underscore the need for a testing prioritization algorithm in view of the MTG publication to serve as reference for both clinicians and pathologists.

Related: Non-Small Cell Lung Cancer Lung Cancer KRAS gene EGFR

Serizawa M, Koh Y, Kenmotsu H, et al.
Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: a prospective, single-institute study.
Cancer. 2014; 120(10):1471-81 [PubMed] Related Publications
BACKGROUND: Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype.
METHODS: Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes (EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions.
RESULTS: Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients.
CONCLUSIONS: This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer.

Related: Lung Cancer KRAS gene EGFR

Busam KJ, Kutzner H, Cerroni L, Wiesner T
Clinical and pathologic findings of Spitz nevi and atypical Spitz tumors with ALK fusions.
Am J Surg Pathol. 2014; 38(7):925-33 [PubMed] Related Publications
Spitz tumors represent a group of melanocytic neoplasms that typically affect young individuals. Microscopically, the lesions are composed of cytologically distinct spindle and epithelioid melanocytes, with a range in the architectural display or the cells, their nuclear features, and secondary epidermal or stromal changes. Recently, kinase fusions have been documented in a subset of Spitz tumors, but there is limited information on the clinical and pathologic features associated with those lesions. Here, we report a series of 17 patients (9 male, 8 female) with spitzoid neoplasms showing ALK fusions (5 Spitz nevi and 12 atypical Spitz tumors). The patients' ages ranged from 2 years to 35 years (mean=17 y; median=16 y). Most lesions were located on the lower extremities and presented clinically as polypoid nodules. All tumors were compound melanocytic proliferations with a predominant intradermal growth. Tumor thickness ranged from 1.1 to 6 mm (mean=2.9 mm; median=2.5 mm). The most characteristic histopathologic feature of the tumors (seen in all but 2 lesions) was a plexiform dermal growth of intersecting fascicles of fusiform melanocytes. All but 2 tumors were amelanotic. All tumors were strongly immunoreactive for ALK. The ALK rearrangements were confirmed in all cases by fluorescence in situ hybridization (FISH), and the fusion partner was determined by quantitative polymerase chain reaction as TPM3 (tropomyosin 3) in 11 cases and DCTN1 (dynactin 1) in 6 cases. None of the 8 tumors that were analyzed by FISH for copy number changes of 6p, 6q, 9p, or 11q met criteria for melanoma. Two patients underwent a sentinel lymph node biopsy, and in both cases melanocyte nests were found in the subcapsular sinus of the node. Array comparative genomic hybridization of these 2 tumors revealed no chromosomal gains or losses. In conclusion, our study revealed that Spitz nevi/tumors with ALK rearrangement show a characteristic plexiform morphology and that ALK immunohistochemistry and FISH enable the accurate identification of this morphologic and genetic distinct subset of spitzoid neoplasms.

Related: FISH Skin Cancer

Smith NE, Deyrup AT, Mariño-Enriquez A, et al.
VCL-ALK renal cell carcinoma in children with sickle-cell trait: the eighth sickle-cell nephropathy?
Am J Surg Pathol. 2014; 38(6):858-63 [PubMed] Related Publications
We report the third case of a renal cell carcinoma bearing a fusion of the vinculin (VCL) and anaplastic lymphoma kinase (ALK) genes. Like the 2 other reported cases, this neoplasm occurred in a young patient (6 y old) with sickle-cell trait and demonstrated distinctive morphologic features including medullary epicenter, discohesive polygonal or spindle-shaped cells with prominent cytoplasmic vacuoles, and prominent lymphocytic infiltrate. The neoplastic cells demonstrated focal membranous labeling for ALK protein by immunohistochemistry, ALK gene rearrangement by fluorescence in situ hybridization, and a specific VCL-ALK gene fusion by reverse transcriptase polymerase chain reaction. VCL-ALK renal cell carcinoma may represent the eighth sickle-cell nephropathy.

Related: FISH Kidney Cancer

Nakamura Y, Taniguchi H, Mizoguchi K, et al.
Secondary EML4-ALK-positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood: a case report.
Jpn J Clin Oncol. 2014; 44(6):593-6 [PubMed] Related Publications
It is widely recognized that the risk of secondary neoplasms increases as childhood cancer survivors progress through adulthood. These are mainly hematological malignancies, and recurrent chromosome translocations are commonly detected in such cases. On the other hand, while secondary epithelial malignancies have sometimes been reported, chromosome translocations in these epithelial malignancies have not. A 33-year-old man who had been diagnosed with acute lymphoblastic leukemia and treated with chemotherapy almost 20 years earlier was diagnosed with lung adenocarcinoma. After chromosomal rearrangement of echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene was detected in this adenocarcinoma, he responded to treatment with crizotinib. It was therefore concluded that this echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase gene-positive lung adenocarcinoma was a secondary epithelial malignancy.

Related: Lung Cancer Acute Lymphocytic Leukemia (ALL) Crizotinib (Xalkori)


Found this page useful?

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. ALK, Cancer Genetics Web: http://www.cancerindex.org/geneweb/ALK.htm Accessed: date

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 14 December, 2014     Cancer Genetics Web, Established 1999