Molecular Epidemiology of  ALK  Rearrangements in Advanced Lung Adenocarcinoma in Latin America

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Abstract

Objective: Latin American countries are heterogeneous in terms of lung cancer incidence and exposure to potential carcinogens. We evaluated the frequency and clinical characteristics of ALK rearrangements ( ALKr) in Latin America. Methods: A total of 5,130 lung cancer patients from 10 Latin American countries were screened for inclusion. ALKr detection was performed by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to assess method variability. Demographic and clinicopathologic characteristics were analyzed. Results: Among the 5,130 patients screened, 8.4% ( n = 433) had nonevaluable FISH tests. Evaluable FISH analyses revealed positive ALKr in 6.8% (320/4,697) of the study population, which included patients from 9 countries. ALKr distribution for each country was: Mexico 7.6% (79/1,034), Colombia 4.1% (10/242), Argentina 6.0% (153/2,534), Costa Rica 9.5% (13/137), Panama 4.4% (5/114), Uruguay 5.4% (2/37), Chile 8.6% (16/185), Venezuela 8.9% (13/146), and Peru 10.8% (29/268). RT-PCR showed high positive (83.6%) and negative (99.7%) predictive values when compared to the gold standard FISH. In contrast, IHC only showed a high negative predictive value (94.6%). Conclusions: Although there is a clear country and continental variability in terms of ALKr frequency, this difference is not significant and the overall incidence of ALKr in Latin America does not differ from the rest of the world.

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Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

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EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.

Jussi P. Koivunen, Craig H. Mermel, Kreshnik Zejnullahu … (2008)

The EML4-ALK fusion gene has been detected in approximately 7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.

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Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.

Kengo Takeuchi, Yoshihiro Yamashita, KENTARO INAMURA … (2008)

EML4-ALK is a fusion-type protein tyrosine kinase that is generated by inv(2)(p21p23) in the genome of non-small cell lung cancer (NSCLC). To allow sensitive detection of EML4-ALK fusion transcripts, we have now developed a multiplex reverse transcription-PCR (RT-PCR) system that captures all in-frame fusions between the two genes. Primers were designed to detect all possible in-frame fusions of EML4 to exon 20 of ALK, and a single-tube multiplex RT-PCR assay was done with total RNA from 656 solid tumors of the lung (n = 364) and 10 other organs. From consecutive lung adenocarcinoma cases (n = 253), we identified 11 specimens (4.35%) positive for fusion transcripts, 9 of which were positive for the previously identified variants 1, 2, and 3. The remaining two specimens harbored novel transcript isoforms in which exon 14 (variant 4) or exon 2 (variant 5) of EML4 was connected to exon 20 of ALK. No fusion transcripts were detected for other types of lung cancer (n = 111) or for tumors from 10 other organs (n = 292). Genomic rearrangements responsible for the fusion events in NSCLC cells were confirmed by genomic PCR analysis and fluorescence in situ hybridization. The novel isoforms of EML4-ALK manifested marked oncogenic activity, and they yielded a pattern of cytoplasmic staining with fine granular foci in immunohistochemical analysis of NSCLC specimens. These data reinforce the importance of accurate diagnosis of EML4-ALK-positive tumors for the optimization of treatment strategies.

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Author and article information

Journal

Journal ID (publisher-id): OCL

Journal ID (nlm-ta): Oncology

Journal ID (doi): 10.1159/issn.0030-2414

Title: Oncology

Publisher: S. Karger AG

ISSN (Print): 0030-2414

ISSN (Electronic): 1423-0232

Publication date Subscription-year: 2019

Publication date (Print): April 2019

Publication date (Electronic): 26 November 2018

Volume: 96

Issue: 4

Pages: 207-216

Affiliations

[_a] _aThoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico

[_b] _bClinical and Translational Oncology Group, Institute of Oncology, Clínica del Country, Bogotá, Colombia

[_c] _cFoundation for Clinical and Applied Cancer Research-FICMAC, Bogotá, Colombia

[_d] _dPharmacy and Biochemistry Faculty, Universidad de Buenos Aires, Buenos Aires, Argentina

[_e] _eFoundation “Investigar”, Buenos Aires, Argentina

[_f] _fMedical Oncology Department, Hospital San Juan de Dios, San Jose, Costa Rica

[_g] _gMedical Oncology Department, Thoracic Oncology Section, Instituto Fleming, Buenos Aires, Argentina

[_h] _hOncología Integral de Alta Especialidad, Hospital ABC, Mexico City, Mexico

[_i] _iInternal Medicine-Medical Oncology Department, National Institute of Cancer, Panama City, Panama

[_j] _jMedical Oncology Department, Universidad de la Republica-UdeLAR, Montevideo, Uruguay

[_k] _kPathology Department, Instituto de Oncología Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina

[_l] _lPathology Department, Hospital Alemán, Buenos Aires, Argentina

[_m] _mPathology Department, Hospital Clínico de la Universidad de Chile, Santiago de Chile, Chile

[_n] _nCentro de Estudios Médicos e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Buenos Aires, Argentina

[_o] _oDepartment of Pathology, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico

[_p] _pInstituto Nacional de Enfermedades Neoplásicas, Surquillo, Peru

[_q] _qMedical Oncology Department, Thoracic Oncology Section, Instituto Oncologico “Dr. Luis Razetti”, Caracas, Venezuela

[_r] _rOncology Department, Centro Javeriano de Oncología, Hospital Universitario San Ignacio, Bogotá, Colombia

[_s] _sDepartment of Pathology, Clínica las Condes, Santiago, Chile

[_t] _tTécnicas Genéticas Aplicadas a la Clínica, Mexico City, Mexico

[_u] _uHospital Ángeles de Puebla. Escuela de Medicina UDLAP (Universidad de las Américas Puebla), Puebla, Mexico

[_v] _vCentro Medico del Noreste, Unidad Médica de Alta Especialidad UMAE, Instituto Mexicano del Seguro Social, Monterrey, Mexico

[_w] _wDepartment of Pathology, Hospital Metropolitano, Guayaquil, Ecuador

[_x] _xConsejo de Nanopharmacia Diagnóstica, Mexico City, Mexico

[_y] _yMemorial Cancer Institute, Memorial Healthcare System, Hollywood, Florida, USA

Author notes

*Dr. Oscar Arrieta, Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Av. San Fernando #22, Sección XVI, Tlalpan, Distrito Federal, Mexico City 14080 (Mexico), E-Mail ogar@unam.mx

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Oscar Arrieta https://orcid.org/0000-0002-1164-3779

Article

Publisher ID: 493733 Other ID: Oncology 2019;96:207–216

DOI: 10.1159/000493733

PubMed ID: 30476928

SO-VID: 4d4f1ca7-6036-40ed-a164-46f491be9ef3

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History

Date received : 17 April 2018

Date accepted : 12 September 2018

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Figures: 2, Tables: 2, Pages: 10

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Molecular Epidemiology of ALK Rearrangements in Advanced Lung Adenocarcinoma in Latin America

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Karger: Oncology

Most cited references 29

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.

Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.

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