RASSF1A gene inactivation in non‐small cell lung cancer and its clinical implication

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Abstract
Methylation‐associated inactivation of RASSF1, a putative tumor suppressor identified at 3p21.3, is reported in several cancers. We examined RASSF1 in non‐small lung cancer (NSCLC) to search for clinical implications. RT‐PCR analysis showed no expression of RASSF1A in 12 of 20 lung cancer cell lines. Loss of expression correlated well with promoter methylation status of these lines. Sequence analysis revealed 2 polymorphisms (codons 21 and 133) in RASSF1A transcripts, but not in RASSF1C transcripts. No somatic mutations were found. Of 7 cell lines with K‐ras mutations at codon 12 or 61, 2 lost expression of RASSF1A, whereas in 13 cell lines with wild‐type K‐ras gene, 10 lost RASSF1A gene expression (p = 0.0521). We investigated methylation status of this putative tumor suppressor gene in 100 primary NSCLCs to determine whether there is a clinical significance. Forty‐two of primary NSCLCs demonstrated methylated allele. There is no correlation between promoter methylation of RASSF1A and clinicopathological findings, including histological type or grade, tumor staging, p53 and K‐ras mutational status, or patients' survival. In the cases of Stage I and II disease, however, RASSF1A methylation was associated with earlier recurrence (p = 0.0247). Epigenetic silencing of RASSF1A is a frequent event in non‐small lung cancer and will provide novel opportunities to develop diagnosis and therapy of NSCLC.