van Baars Romy, van der Marel Jacolien, Snijders Peter J F, Rodriquez-Manfredi Agata, ter Harmsel Bram, van den Munckhof Henk A M, Ordi Jaume, del Pino Marta, van de Sandt Miekel M, Wentzensen N, Meijer Chris J L M, Quint Wim G V
DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Int J Cancer. 2016 Jan 15;138(2):463-71. doi: 10.1002/ijc.29706. Epub 2015 Aug 14.
Recent studies have shown that CADM1/MAL methylation levels in cervical scrapes increase with severity and duration of the underlying cervical intraepithelial neoplasia (CIN) lesion. Multiple lesions of different histological grades and duration are frequently present on the cervix. To gain more insight into the possible epigenetic heterogeneity and its consequences for the methylation status in cervical scrapes, we performed an exploratory study of CADM1/MAL methylation in different grades of CIN lesions present in women with multiple cervical biopsies. CADM1-M18 and MAL-M1 methylation was assessed using a standardised, multiplex, quantitative methylation specific PCR on 178 biopsies with various grades of CIN in 65 women, and in their corresponding cervical scrapes. CADM1/MAL methylation positivity increased with disease severity, from 5.5% in normal biopsies to 63.3% and 100% in biopsies with CIN3 and cervical cancer, respectively. In the majority (8/9) of women where besides a CIN2/3 lesion a biopsy from normal cervical tissue was present, the CIN2/3 biopsy was CADM1/MAL methylation positive and the normal biopsy was CADM1/MAL methylation negative. A good concordance (78%) was found between CADM1/MAL methylation results on the scrapes and the biopsy with the worst diagnosis, particularly between samples of women with CIN3 and cervical cancer (92% and 100% concordance, respectively). Thus, in women with multiple cervical biopsies, CADM1/MAL methylation increases with severity of the lesion and is lesion-specific. CADM1/MAL methylation status in cervical scrapes appears to be representative of the worst underlying lesion, particularly for CIN3 and cervical cancer.
近期研究表明，宫颈刮片中CADM1/MAL甲基化水平随潜在宫颈上皮内瘤变（CIN）病变的严重程度和持续时间增加。宫颈上经常存在不同组织学分级和持续时间的多个病变。为了更深入了解宫颈刮片中可能存在的表观遗传异质性及其对甲基化状态的影响，我们对接受多次宫颈活检的女性中不同分级CIN病变的CADM1/MAL甲基化进行了一项探索性研究。使用标准化的多重定量甲基化特异性PCR对65名女性的178份不同分级CIN的活检样本及其相应的宫颈刮片样本评估CADM1-M18和MAL-M1甲基化。CADM1/MAL甲基化阳性率随疾病严重程度增加，从正常活检中的5.5%分别增至CIN3活检中的63.3%和宫颈癌活检中的100%。在大多数（8/9）除CIN2/3病变外还存在正常宫颈组织活检的女性中，CIN2/3活检样本的CADM1/MAL甲基化呈阳性，而正常活检样本的CADM1/MAL甲基化呈阴性。宫颈刮片与诊断最差的活检样本之间的CADM1/MAL甲基化结果具有良好的一致性（78%），尤其是CIN3和宫颈癌女性的样本之间（一致性分别为92%和100%）。因此，在接受多次宫颈活检的女性中，CADM1/MAL甲基化随病变严重程度增加且具有病变特异性。宫颈刮片中CADM1/MAL甲基化状态似乎代表了最严重的潜在病变，特别是对于CIN3和宫颈癌。
