BackgroundBreast carcinogenesis is a multistep process involving genetic and epigenetic changes. Tumor tissues are frequently characterized by gene-specific hypermethylation and global DNA hypomethylation. Aberrant DNA methylation levels have, however, not only been found in tumors, but also in tumor-surrounding tissue appearing histologically normal. This phenomenon is called field cancerization. Knowledge of the existence of a cancer field and its spread are of clinical relevance. If the tissue showing pre-neoplastic lesions is not removed by surgery, it may develop into invasive carcinoma.MethodsWe investigated the prevalence of gene-specific and global DNA methylation changes in tumor-adjacent and tumor-distant tissues in comparison to tumor tissues from the same breast cancer patients (n = 18) and normal breast tissues from healthy women (n = 4). Methylation-sensitive high resolution melting (MS-HRM) analysis was applied to determine methylation levels in the promoters of APC, BRCA1, CDKN2A (p16), ESR1, HER2/neu and PTEN, in CDKN2A exon 2 and in LINE-1, as indicator for the global DNA methylation extent. The methylation status of the ESR2 promoter was determined by pyrosequencing.ResultsTumor-adjacent and tumor-distant tissues frequently showed pre-neoplastic gene-specific and global DNA methylation changes. The APC promoter (p = 0.003) and exon 2 of CDKN2A (p < 0.001) were significantly higher methylated in tumors than in normal breast tissues from healthy women. For both regions, significant differences were also found between tumor and tumor-adjacent tissues (p = 0.001 and p < 0.001, respectively) and tumor and tumor-distant tissues (p = 0.001 and p < 0.001, respectively) from breast cancer patients. In addition, tumor-adjacent (p = 0.002) and tumor-distant tissues (p = 0.005) showed significantly higher methylation levels of CDKN2A exon 2 than normal breast tissues serving as control. Significant correlations were found between the proliferative activity and the methylation status of CDKN2A exon 2 in tumor (r = −0.485, p = 0.041) and tumor-distant tissues (r = −0.498, p = 0.036).ConclusionsFrom our results we can conclude that methylation changes in CDKN2A exon 2 are associated with breast carcinogenesis. Further investigations are, however, necessary to confirm that hypermethylation of CDKN2A exon 2 is associated with tumor proliferative activity.
The purpose of this study is to report the organization of a cost-effective screening program for cervical cancer in a developing country such as Brazil. The Cervical Cancer Screening Program of Paraná (CCSPP) was launched in October 1997 and was the result of a joint collaboration between the government of Paraná (Secretary of Health of the State of Paraná), scientific societies (pathologists, gynecologists, and nurses), and a non governmental organization called the Women's Popular Forum of Paraná. The main goal of the program was to enhance the Papanicolaou (Pap) smear screening to coverage up to 85% of female adult population with a 3-yr interval between examinations, as well as to reduce the incidence and mortality from cervical cancer in the state of Paraná, a Southern state of Brazil. The cytological findings in all Pap smears recorded in a central computer-based register during 5 yr of the program (October 1997-October 2002) are discussed. During that period, 2,244,158 Pap smears were performed in women included in the program from the 398 cities of the state of Paraná. The cytological smears were analyzed according to the Bethesda System. The previous year, before the program was launched, a Pap smear was taken from 43% of women of Paraná. At the end of 5 yr, coverage was increased to around 86%. The great majority of examinations had a negative result (98%). Only 2% of examinations had cytological abnormalities (n = 44,621). Low-grade lesions predominated in women aged 15-30 yr, and the high-grade lesions were more common in women aged 25-45 yr. Patients older than 40 yr had the greatest incidence of invasive cancer. Although the program is only 5 yr old, a decrease in the mortality from cervical cancer in women from Paraná is clearly apparent: in 1998, 297 women died of cervical cancer, as compared with 188 as of September 2002.
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