Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter1A in breast and lung carcinomas

The adenomatous polyposis coli (APC) gene is a tumor suppressor gene associ ated with both familial and sporadic cancer. Despite high rates of allelic loss in lung and breast cancers, point mutations of the APC gene are infreq uent in these cancer types. Aberrant methylation of the APC promoter 1A occ urs in some colorectal and gastric malignancies, and we investigated whethe r the same mechanism occurs in lung and breast cancers, The methylation sta tus of the APC gene promoter 1A was analyzed in 77 breast, 50 small cell (S CLC), and 106 non-small cell (NSCLC) lung cancer tumors and cell lines and in 68 nonmalignant tissues by methylation-specific PCR, Expression of the A PC promoter 1A transcript was examined in a subset of cell lines by reverse transcription-PCR, and loss of heterozygosity at the gene locus was analyz ed by the use of 12 microsatellite and polymorphic markers, Statistical tes ts were two-sided. Promoter 1A was methylated in 34 of 77 breast cancer tum ors and cell lines (44%), in 56 of 106 NSCLC tumors and cell lines (53%), i n 13 of 50 SCLC cell lines (26%), and in 3 of 68 nonmalignant samples (4%). Most cell lines tested contained the unmethylated or methylated form exclu sively, In 27 cell lines tested, there was complete concordance between pro moter methylation and silencing of its transcript. Demethylation with 5-aza -2 ' -deoxycytidine treatment restored transcript 1A expression in all eigh t methylated cell lines tested. Loss of heterozygosity at the APC locus was observed in 85% of SCLCs, 83% of NSCLCs, and 63% of breast cancer cell lin es. The frequency of methylation in breast cancers increased with tumor sta ge and size. In summary, aberrant methylation of the 1A promoter of the APC gene and loss of its specific transcript is frequently present in breast a nd NSCLC cancers and cell lines and, to a lesser extent, in SCLC cell lines . Our findings may be of biological and clinical importance.