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Background   RASSF1A  gene silencing by DNA methylation has been suggested as a major event in pancreatic endocrine tumor (PET) but  RASSF1A  expression has never been studied. The  RASSF1  locus contains two CpG islands ( A  and  C ) and generates seven transcripts ( RASSF1A - RASSF1G ) by differential promoter usage and alternative splicing.    Methods  We studied 20 primary PETs, their matched normal pancreas and three PET cell lines for the (i) methylation status of the  RASSF1  CpG islands using methylation-specific PCR and pyrosequencing and (ii) expression of  RASSF1  isoforms by quantitative RT-PCR in 13 cases. CpG island A methylation was evaluated by methylation-specific PCR (MSP) and by quantitative methylation-specific PCR (qMSP); pyrosequencing was applied to quantify the methylation of 51 CpGs also encompassing those explored by MSP and qMSP approaches.    Results  MSP detected methylation in 16/20 (80%) PETs and 13/20 (65%) normal pancreas. At qMSP, 11/20 PETs (55%) and 9/20 (45%) normals were methylated in at least 20% of  RASSF1A  alleles.  Pyrosequencing showed variable distribution and levels of methylation within and among samples, with PETs having average methylation higher than normals in 15/20 (75%) cases ( P  = 0.01). The evaluation of mRNA expression of  RASSF1  variants showed that: i)  RASSF1A  was always expressed in PET and normal tissues, but it was, on average, expressed 6.8 times less in PET ( P  = 0.003); ii)  RASSF1A  methylation inversely correlated with its expression; iii)  RASSF1  isoforms were rarely found, except for  RASSF1B  that was always expressed and  RASSF1C  whose expression was 11.4 times higher in PET than in normal tissue ( P  = 0.001). A correlation between  RASSF1A  expression and gene methylation was found in two of the three PET cell lines, which also showed a significant increase in  RASSF1A  expression upon demethylating treatment.    Conclusions   RASSF1A  gene methylation in PET is higher than normal pancreas in no more than 75% of cases and as such it cannot be considered a marker for this neoplasm.  RASSF1A  is always expressed in PET and normal pancreas and its levels are inversely correlated with gene methylation. Isoform  RASSF1C  is overexpressed in PET and the recent demonstration of its involvement in the regulation of the Wnt pathway points to a potential pathogenetic role in tumor development.

Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1Cin pancreatic endocrine tumors