Frequent BRG1/SMARCA4–inactivating mutations in human lung cancer cell lines

Authors

  • Pedro P. Medina,

    1. Lung Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
    Current affiliation:
    1. Department of Molecular, Cellular and Developmental Biology, Yale University KBT 938, 266 Whitney Ave, New Haven, CT 06520
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  • Octavio A. Romero,

    1. Lung Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
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  • Takashi Kohno,

    1. Biology Division, National Cancer Center Research Institute, Tokyo, Japan
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  • Luis M. Montuenga,

    1. Division of Oncology, Centro para la Investigacion Medica Aplicada (CIMA), University of Navarra, Pamplona, Spain
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  • Ruben Pio,

    1. Division of Oncology, Centro para la Investigacion Medica Aplicada (CIMA), University of Navarra, Pamplona, Spain
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  • Jun Yokota,

    1. Biology Division, National Cancer Center Research Institute, Tokyo, Japan
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  • Montse Sanchez-Cespedes

    Corresponding author
    1. Lung Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
    • Lung Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain
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  • Communicated by David E. Goldgar

Abstract

Components of the SWI/SNF chromatin-remodeling complex, such as INI1, are inactivated in human cancer and, thus, act as tumor suppressors. Here we screened for mutations the entire coding sequence of BRG1 (SMARCA4), which encodes the ATPase of the complex, in 59 lung cancer cell lines of the most common histopathological types. Mutations were detected in 24% of the cancer cell lines, many of them in cells commonly used for lung cancer research. All mutations were homozygous and most predicted truncated proteins. The alterations were significantly more frequent in the non-small-cell lung cancer (NSCLC) type (13/37, 35%) as compared to the small-cell lung cancer (SCLC) type (1/19, 5%) (P<0.05; Fisher's Exact test) and BRG1 was the fourth most frequently altered gene in NSCLC cell lines. BRG1 mutations coexisted with mutations/deletions at KRAS, LKB1, NRAS, P16, and P53. However, alterations at BRG1 always occurred in the absence of MYC amplification, suggesting a common role in lung cancer development. In conclusion, our data strongly support that BRG1 is a bona fide tumor suppressor and a major factor in lung tumorigenesis. Hum Mutat 29(5), 617–622, 2008. © 2008 Wiley-Liss, Inc.

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