Adenomatous polyposis coli 1A is likely to be methylated as a passenger in human gastric carcinogenesis

Abstract

Many promoter CpG islands (CGIs) are methylated as a consequence of or in association with carcinogenesis (passenger), in addition to being a cause of carcinogenesis (driver). In gastric cancers, promoter 1A of the adenomatous polyposis coli (APC) gene is frequently methylated, and is often discussed as a driver. However, the actual role of 1A methylation is unclear because the same APC protein is coded by two transcripts from two promoters, 1A and 1B, and their relative expression levels in gastric mucosae have not been quantified. To clarify this issue, we first identified detailed transcription start sites of 1A and 1B transcripts. We then confirmed that, among nine gastric cancer cell lines, 1A methylation, if present, could repress 1A transcription while 1B was expressed and not methylated. In primary samples, 1B expression was 15-fold higher than 1A expression in gastric mucosae of healthy volunteers, and was decreased markedly in non-cancerous gastric mucosae of cancer patients. Quantitative methylation analysis showed that promoter 1A was methylated at similar levels (20-40%) in healthy individuals and non-cancerous gastric mucosae of cancer patients, and promoter 1B was never methylated in any samples, including gastric cancers. These findings strongly indicated that methylation of APC promoter 1A is a passenger, and suggested that marked down-regulation of 1B expression could be related to formation of a field predisposed to gastric cancers.