DNA methylation profiling of phyllodes and fibroadenoma tumours of the breast
DNA methylation profiling of phyllodes and fibroadenoma tumours of the breast
复制标题
DOI：
10.1007/s10549-010-0970-4
复制
发表时间：
2010-11-01
影响因子：
3.8
通讯作者：
Fox, Stephen B.
中科院分区：
文献类型：
--
作者：
Huang, Katie T.;Dobrovic, Alexander;Fox, Stephen B.
叶状肿瘤和细胞性纤维腺瘤都是乳腺纤维上皮肿瘤。与纤维腺瘤不同，叶状肿瘤具有复发和转移的能力。虽然这些病变可以通过间质细胞结构、有丝分裂指数、是否存在间质过度生长和细胞增生来区分，但仍有重叠，并且经常无法做出明确诊断，特别是在活检时。我们试图评估使用已知在癌症中甲基化的选定基因的DNA启动子甲基化谱是否能让我们更多地了解这些肿瘤的生物学，以及它是否能识别甲基化标记物，这些标记物可以区分叶状肿瘤和纤维腺瘤和/或区分不同级别的叶状肿瘤。应用甲基化敏感高分辨熔解曲线（MS-HRM）检测86例叶状肿瘤（良性15例，交界性28例，恶性43例）和26例纤维腺瘤的启动子DNA甲基化改变。测试了一组11个基因（RASSF 1A、TWIST 1、APC、WIF 1、MGMT、MAL、RAR β、CDKN 2A、CDH 1、TP 73和MLH 1）。甲基化状态与组织学和临床病理参数相关。其中5个基因启动子在一定比例的叶状肿瘤中显示出一定程度的甲基化：RASSF 1A，45.3%; TWIST 1，10.7%; APC，4.1%; WIF 1，2.9%和MGMT，1.3%。只有两个基因在纤维腺瘤中表现出任何甲基化，通常在背景水平; RASSF 1A，53.8%和MGMT，8.3%。与以前的报道相反，在两种肿瘤类型中均未观察到CDKN 2A甲基化。总的来说，甲基化模式与正常细胞中可能看到的差异很小。然而，在一些叶状肿瘤中观察到RASSF 1A（24.4%）和TWIST 1（7.1%）的显著甲基化水平。与纤维腺瘤相比，RASSF 1A和/或TWIST 1甲基化升高与叶状肿瘤显著相关（P = 0.02），TWIST 1甲基化与叶状肿瘤恶性程度增加相关（P < 0.001）。总之，评估RASSF 1A和TWIST 1的甲基化可能有助于叶状肿瘤的诊断。在纤维腺瘤中缺乏频繁的甲基化支持非肿瘤性起源。
Phyllodes tumours and cellular fibroadenomas are both fibroepithelial tumours of the breast. Phyllodes tumours, unlike fibroadenomas, have the ability to recur and metastasise. Although these lesions can be distinguished by their stromal cellularity, mitotic index, presence or absence of stromal overgrowth and cellular atypia, there is overlap and not infrequently a definitive diagnosis cannot be made, particularly on biopsy. We sought to evaluate whether DNA promoter methylation profiling using selected genes known to be methylated in cancer would allow us to learn more about the biology of these tumours, and whether it could identify methylation markers that could differentiate phyllodes tumours from fibroadenomas and/or distinguish phyllodes tumours of different grades. Methylation-sensitive high resolution melting (MS-HRM) was used to screen promoter DNA methylation changes in 86 phyllodes tumours (15 benign, 28 borderline, 43 malignant) and 26 fibroadenomas. A panel of 11 genes (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, RAR beta, CDKN2A, CDH1, TP73 and MLH1) was tested. Methylation status was correlated with histology and with clinicopathological parameters. Five of the gene promoters showed some methylation in a proportion of phyllodes tumours; RASSF1A, 45.3%; TWIST1, 10.7%; APC, 4.1%; WIF1, 2.9% and MGMT, 1.3%. Only two genes showed any methylation in fibroadenomas usually at background levels; RASSF1A, 53.8% and MGMT, 8.3%. No CDKN2A methylation was observed in either tumour type, contrary to previous reports. Overall, the methylation patterns differed little from that which might be seen in normal cells. However, significant levels of methylation of RASSF1A (24.4%) and TWIST1 (7.1%) was observed in some phyllodes tumours. Elevated RASSF1A and/or TWIST1 methylation was significantly associated with phyllodes tumours compared with fibroadenomas (P = 0.02), TWIST1 methylation correlated with increasing malignancy in phyllodes tumours (P < 0.001). In conclusion, assessment of methylation of RASSF1A and TWIST1 may aid in the diagnosis of phyllodes tumours. The absence of frequent methylation in fibroadenomas supports a non-neoplastic origin.