Aberrant methylation status of known methylation‐sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c‐kit and PDGFRA gene mutations and their malignancy

To identify additional alterations to c‐kit or platelet‐derived growth factor receptor α ( PDGFRA ) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation‐sensitive CpG islands ( p15 , p16 , p73 , 0‐6‐methylguanine‐DNA methyltransferase, E‐cadherin , mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [ MINT ] 1 , MINT2 , and MINT31 ), and compared the results with the malignant potential and gain‐of‐function mutation types of GIST. Thirty‐five GIST ( c‐kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation‐specific polymerase chain reaction to detect the methylation status of the nine methylation‐sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1 , 60%; MINT2 , 51%; MGMT , 49%; p73 , 49%; p16 , 20%; E‐cadherin , 14%; MINT1 , 9%; p15 , 6%; and MINT31 , 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c‐kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low‐risk GIST, and in 58% of high‐risk GIST. Our results suggested that in addition to c‐kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch‐repair genes, may have a role in the tumorigenesis of GIST. ( Cancer Sci 2008; 99: 253–259)