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The Candidate Tumor Suppressor Gene, RASSF1A, from Human Chromosome 3p21.3 is Involved in Kidney Tumorigenesis
Koen Dreijerink, Eleonora Braga, Igor Kuzmin, Laura Geil, Fuh-Mei Duh, Debora Angeloni, Berton Zbar, Michael I. Lerman, Eric J. Stanbridge, John D. Minna, Alexei Protopopov, Jingfeng Li, Vladimir Kashuba, George Klein and Eugene R. Zabarovsky
Proceedings of the National Academy of Sciences of the United States of America
Vol. 98, No. 13 (Jun. 19, 2001), pp. 7504-7509
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3056018
Page Count: 6
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Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91%). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2′-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.
Proceedings of the National Academy of Sciences of the United States of America © 2001 National Academy of Sciences