Aberrant methylation of <i>p16</i> <sup>INK4a</sup> is an early event in lung cancer and a potential biomarker for early diagnosis

DOI Web Site 被引用文献19件
  • Steven A. Belinsky
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231
  • Kristen J. Nikula
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231
  • William A. Palmisano
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231
  • Ruth Michels
  • Geno Saccomanno
  • Edward Gabrielson
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231
  • Stephen B. Baylin
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231
  • James G. Herman
    Lovelace Respiratory Research Institute, Lung Cancer Program, P.O. Box 5890, Albuquerque, NM 87185; St. Mary’s Hospital, 2635 North 7th, Grand Junction, CO 81501; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, 424 North Bond Street, Baltimore, MD 21231

説明

<jats:p> The <jats:italic>p16</jats:italic> <jats:sup>INK4a</jats:sup> ( <jats:italic>p16</jats:italic> ) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including lung cancer, the leading cause of cancer-related deaths in the U.S. We have determined the timing of this event in an animal model of lung carcinogenesis and in human squamous cell carcinomas (SCCs). In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the <jats:italic>p16</jats:italic> gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions. The timing for <jats:italic>p16</jats:italic> methylation was recapitulated in human SCCs where the <jats:italic>p16</jats:italic> gene was coordinately methylated in 75% of carcinoma <jats:italic>in situ</jats:italic> lesions adjacent to SCCs harboring this change. Moreover, the frequency of this event increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma <jats:italic>in situ</jats:italic> (50%) lesions. Methylation of <jats:italic>p16</jats:italic> was associated with loss of expression in both tumors and precursor lesions indicating that both alleles were functionally inactivated. The potential of using assays for aberrant <jats:italic>p16</jats:italic> methylation to identify disease and/or risk was validated by detection of this change in sputum from three of seven patients with cancer and 5 of 26 cancer-free individuals at high risk. These studies show for the first time that an epigenetic alteration, aberrant methylation of the <jats:italic>p16</jats:italic> gene, can be an early event in lung cancer and may constitute a new biomarker for early detection and monitoring of prevention trials. </jats:p>

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