Wisman G Bea A, Nijhuis Esther R, Hoque Mohammad O, Reesink-Peters Nathalie, Koning Alice J, Volders Haukeline H, Buikema Henk J, Boezen H Marike, Hollema Harry, Schuuring Ed, Sidransky David, van der Zee Ate G J
Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
Int J Cancer. 2006 Oct 15;119(8):1908-14. doi: 10.1002/ijc.22060.
Current cervical cancer screening is based on morphological assessment of Pap smears and associated with significant false negative and false positive results. Previously, we have shown that detection of hypermethylated genes in cervical scrapings using quantitative methylation-specific PCR (QMSP) is a promising tool for identification of squamous cell cervical cancer. Aim of the present pilot-study was to evaluate presence of hypermethylated genes in cervical carcinogenesis, both in squamous cell as well as adenocarcinomas. Cervical scrapings were obtained from 30 patients diagnosed with cervical cancer (20 squamous cell carcinomas and 10 adenocarcinomas) and 19 women with histologically normal cervices. The scraped cells were used for determination of promoter hypermethylation by QMSP for 12 genes and for morphological assessment. Overall, CALCA, DAPK, ESR1, TIMP3, APC and RAR-beta2 promoters were significantly more often hypermethylated in cancers than in controls, while adenocarcinomas were more often hypermethylated above the highest control ratio for APC, TIMP3 and RASSF1A promoters. Combining 4 genes (CALCA, DAPK, ESR1 and APC) yielded a sensitivity of 89% (with all adenocarcinomas identified), equal to cytomorphology (89%) and high-risk human papilloma virus (Hr-HPV; 90%). The 4-gene QMSP proved theoretically superior to cytomorphology as well as Hr-HPV in specificity (100% vs. 83 and 68%, respectively), because cytology identified 3 controls as moderate or severe dyskaryosis and 6 controls were positive for Hr-HPV. In conclusions, QMSP of 4 gene promoters combined appears to have comparable sensitivity and potentially better specificity in comparison to "classic" cytomorphological assessment and Hr-HPV detection. QMSP holds promise as a new diagnostic tool for both squamous cell carcinoma and adenocarcinoma of the cervix.
当前的宫颈癌筛查基于巴氏涂片的形态学评估，存在显著的假阴性和假阳性结果。此前，我们已经表明，使用定量甲基化特异性PCR（QMSP）检测宫颈刮片中的高甲基化基因是鉴定宫颈鳞状细胞癌的一种有前景的工具。本初步研究的目的是评估高甲基化基因在宫颈鳞状细胞癌和腺癌发生过程中的存在情况。从30例诊断为宫颈癌的患者（20例鳞状细胞癌和10例腺癌）以及19例组织学宫颈正常的女性中获取宫颈刮片。刮取的细胞用于通过QMSP测定12个基因的启动子高甲基化情况以及进行形态学评估。总体而言，CALCA、DAPK、ESR1、TIMP3、APC和RAR-β2启动子在癌症中的高甲基化频率显著高于对照组，而腺癌中APC、TIMP3和RASSF1A启动子的高甲基化频率高于最高对照组比例。联合检测4个基因（CALCA、DAPK、ESR1和APC）的敏感性为89%（所有腺癌均被检出），与细胞形态学（89%）和高危型人乳头瘤病毒（Hr-HPV；90%）相当。理论上，4基因QMSP在特异性方面优于细胞形态学和Hr-HPV（分别为100%对83%和68%），因为细胞学将3例对照鉴定为中度或重度核异质，6例对照Hr-HPV检测呈阳性。总之，与“经典”细胞形态学评估和Hr-HPV检测相比，联合检测4个基因启动子的QMSP似乎具有相当的敏感性和潜在更好的特异性。QMSP有望成为宫颈鳞状细胞癌和腺癌的一种新诊断工具。
