RASSF1A gene inactivation in non-small cell lung cancer and its clinical implication.
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.
Endoh
Hideki
H
Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
Yatabe
Yasushi
Y
Shimizu
Shigeki
S
Tajima
Kohei
K
Kuwano
Hiroyuki
H
Takahashi
Takashi
T
Mitsudomi
Tetsuya
T
D000368:Aged; D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins