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  • Title: Epigenetic inactivation of laminin-5-encoding genes in lung cancers.
    Author: Sathyanarayana UG, Toyooka S, Padar A, Takahashi T, Brambilla E, Minna JD, Gazdar AF.
    Journal: Clin Cancer Res; 2003 Jul; 9(7):2665-72. PubMed ID: 12855645.
    Abstract:
    PURPOSE: We investigated the loss of expression of three laminin-5 (LN5)-encoding genes in lung cancer cell lines and elucidated the mechanism of inactivation of the genes in lung cancer cell lines and tumors. EXPERIMENTAL DESIGN: We examined the expression of LN5-encoding genes by reverse transcription-PCR in 49 lung cancer cell lines. To elucidate the mechanism of gene silencing, we treated expression-negative cell lines (two for each gene) with a demethylating agent and examined the restoration of expression by reverse transcription-PCR. We dissected out the methylation patterns of CpG sites unique to the promoter regions of LN5-encoding genes by bisulfite genomic sequencing of expression-negative cell lines. We designed methylation-specific primers and validated the methylation status of the promoter regions in lung cancer cell lines using methylation-specific PCR. We further studied the methylation patterns of primary non-small cell lung cancer [NSCLC (n = 36)], small cell lung cancer [SCLC (n = 26)], and carcinoids (n = 24) tumors. RESULTS: We observed frequent losses of expression in NSCLC (20-60%) and SCLC (65-86%) cell lines. Expression of one or more genes was lost in 90% of SCLC cell lines and 65% of NSCLC cell lines. Treatment of expression-negative cell lines with demethylating agent restored expression in all of the cases. Methylation of LN5-encoding genes was present more frequently in SCLC cell lines (60-80%) than in NSCLC cell lines (15-60%), and at least one gene was methylated in 95% of SCLC and 60% of NSCLC cell lines. The concordances between loss of expression and methylation in 40 lung cancer cell lines for the three genes (90-95%) were statistically significant. Methylation was more frequent in SCLC tumors (58-77%) than in NSCLC tumors (22-42%) and carcinoids (13-33%), and at least one gene was methylated in 92% of SCLC tumors, 47% of NSCLC tumors, and 33% of carcinoids. CONCLUSIONS: Our results demonstrate frequent epigenetic inactivation of LN5-encoding genes in lung cancers, and these findings are of biological interest and are potentially of clinical importance.
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