The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas

Loss of heterozygosity at 3p21.3 occurs in more than 90% of small cell lung carcinomas (SCLCs). The Ras association domain family 1 (RASSF1) gene clon ed from the lung tumor suppressor locus 3p21.3 consists of two major altern ative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A (RASSF1A) was observed in 40% of primary non-small cell lung carcinomas a nd in several tumor cell lines. Transfection of RASSF1A suppressed the grow th of lung cancer cells in vitro and in nude mice. Here we have analysed th e methylation status of the CPG island promoters of RASSF1A and RASSF1C in primary SCLCs. In 22 of 28 SCLCs (=79%) the promoter of RASSF1A was highly methylated at all CpG sites analysed, None of the SCLCs showed evidence for methylation of the CpG island of RASSF1C. The results suggest that hyperme thylation of the CpG island promoter of the RASSF1A gene is associated with SCLC pathogenesis.