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Large-scale Transcriptome Analyses Reveal New Genetic Marker Candidates of Head, Neck, and Thyroid Cancer

¹ Departamento de Bioquímica, ² Laboratório de Bioinformática, Instituto de Química, ³ Laboratório de Neurociências (LIM-27), Instituto e Departamento de Psiquiatria, and ⁴ Disciplina de Oncologia, Departamento de Radiologia, Faculdade de Medicina, Universidade de São Paulo; ⁵ Laboratório de Endocrinologia Molecular, Departamentos de Medicina e Morfologia, Universidade Federal de São Paulo; ⁶ Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital do Câncer A.C. Camargo, São Paulo, SP, Brazil; Laboratórios de ⁷ Biologia Molecular e Genômica, Hemocentro and ⁸ Genômica e Expressão, Departamento de Genética e Evolução, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil; ⁹ Departamento de Biologia, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista; ¹⁰ Departamento de Biologia Molecular, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil; and ¹¹ Departamento de Ciências Biológicas, Escola de Farmácia, Universidade Estadual Paulista, Araraquara, SP, Brazil

Requests for reprints: Emmanuel Dias-Neto, Laboratory of Neurosciences (LIM-27), Instituto de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, R. Dr. Ovidio de Campos, s/n Consolação 05403-010, São Paulo, SP, Brazil. Phone: 55-11-3069-7267; Fax: 55-11-3069-8010; E-mail: emmanuel{at}usp.br.

A detailed genome mapping analysis of 213,636 expressed sequence tags (EST) derived from nontumor and tumor tissues of the oral cavity, larynx, pharynx, and thyroid was done. Transcripts matching known human genes were identified; potential new splice variants were flagged and subjected to manual curation, pointing to 788 putatively new alternative splicing isoforms, the majority (75%) being insertion events. A subset of 34 new splicing isoforms (5% of 788 events) was selected and 23 (68%) were confirmed by reverse transcription–PCR and DNA sequencing. Putative new genes were revealed, including six transcripts mapped to well-studied chromosomes such as 22, as well as transcripts that mapped to 253 intergenic regions. In addition, 2,251 noncoding intronic RNAs, eventually involved in transcriptional regulation, were found. A set of 250 candidate markers for loss of heterozygosis or gene amplification was selected by identifying transcripts that mapped to genomic regions previously known to be frequently amplified or deleted in head, neck, and thyroid tumors. Three of these markers were evaluated by quantitative reverse transcription–PCR in an independent set of individual samples. Along with detailed clinical data about tumor origin, the information reported here is now publicly available on a dedicated Web site as a resource for further biological investigation. This first in silico reconstruction of the head, neck, and thyroid transcriptomes points to a wealth of new candidate markers that can be used for future studies on the molecular basis of these tumors. Similar analysis is warranted for a number of other tumors for which large EST data sets are available.

Key Words: head and neck • HNSCC • thyroid • goiter • cancer • ORESTES • ESTs • transcriptome • alternative splicing • tumor markers

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