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      Identification of a Recurrent STRN/ALK Fusion in Thyroid Carcinomas

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          Abstract

          Thyroid carcinoma is the most common endocrine malignant tumor and accounts for 1% of all new malignant diseases. Among all types and subtypes of thyroid cancers that have been described so far, papillary thyroid carcinoma is the most frequent. The standard management treatment of these tumors consists of surgery, followed by radioiodine treatment in case of high risk of relapse. The most aggressive forms are commonly treated by chemotherapy, radiotherapy or experimental drug testing. We recently reported the case of a patient presenting an anaplastic thyroid carcinoma with lung metastases. Fluorescence in situ hybridization analysis allowed us to detect a rearrangement of the anaplastic lymphoma kinase ( ALK) gene in both tumors. The patient was treated with crizotinib and presented an excellent drug response. We present here the subsequent investigations carried out to further characterize this genetic alteration and to assess the prevalence of ALK rearrangements in thyroid lesions. High resolution array-comparative genomic hybridization data complemented by RT-PCR and sequencing analyses, allowed us to demonstrate the presence of a STRN/ALK fusion. The STRN/ALK transcript consisted of the fusion between exon 3 of STRN and exon 20 of ALK. Subsequent screening of 75 various thyroid tumors by RT-PCR revealed that 2 out of 29 papillary thyroid carcinomas exhibited the same fusion transcript. None was detected in other types of malignant or benign thyroid lesions analyzed. These findings could pave the way for the development of new targeted therapeutic strategies in the treatment of papillary thyroid carcinomas and point to ALK inhibitors as promising agents that merit rapid evaluation.

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          Most cited references20

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          Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

          The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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            Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

            The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.
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              Thyroid carcinoma.

              Thyroid carcinomas are fairly uncommon and include disease types that range from indolent localised papillary carcinomas to the fulminant and lethal anaplastic disease. Several attempts to formulate a consensus about treatment of thyroid carcinoma have resulted in published guidelines for diagnosis and initial disease management. Multimodality treatments are widely recommended, although there is little evidence from prospective trials to support this approach. Surgical resection to achieve local disease control remains the cornerstone of primary treatment for most thyroid cancers, and is often followed by adjuvant radioiodine treatment for papillary and follicular types of disease. Thyroid hormone replacement therapy is used not only to rectify postsurgical hypothyroidism, but also because there is evidence to suggest that high doses that suppress thyroid stimulating hormone prevent disease recurrence in patients with papillary or follicular carcinomas. Treatment for progressive metastatic disease is often of limited benefit, and there is a pressing need for novel approaches in treatment of patients at high risk of disease-related death. In families with inherited thyroid cancer syndromes, early diagnosis and intervention based on genetic testing might prevent poor disease outcomes. Care should be carefully coordinated by members of an experienced multidisciplinary team, and patients should be provided with education about diagnosis, prognosis, and treatment options to allow them to make informed contributions to decisions about their care.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                27 January 2014
                : 9
                : 1
                : e87170
                Affiliations
                [1 ]Department of Biopathology, Institut Bergonié, Bordeaux, France
                [2 ]INSERM U916, Institut Bergonié, Bordeaux, France
                [3 ]INSERM U694, Institut Biologie Santé, Angers, France
                [4 ]Department of Nuclear Medicine, Institut Bergonié, Bordeaux, France
                [5 ]Translational Research, Institut Bergonié, Bordeaux, France
                Ohio State University Medical Center, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GP IS FB YG FC. Performed the experiments: GP AR NB IH. Analyzed the data: GP IS BB FC. Contributed reagents/materials/analysis tools: FS. Wrote the paper: GP IS FC.

                Article
                PONE-D-13-41164
                10.1371/journal.pone.0087170
                3903624
                24475247
                93534ee5-7f9c-47d9-a094-1e3b5a804005
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 September 2013
                : 18 December 2013
                Page count
                Pages: 9
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology
                Genetics
                Human Genetics
                Personalized Medicine
                Cancer Genetics
                Medicine
                Clinical Genetics
                Personalized Medicine
                Clinical Research Design
                Epidemiology
                Epidemiology
                Cancer Epidemiology
                Clinical Epidemiology
                Genetic Epidemiology
                Oncology
                Basic Cancer Research
                Tumor Physiology
                Cancers and Neoplasms
                Endocrine Tumors
                Thyroid, Papillary Carcinoma

                Uncategorized
                Uncategorized

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