Lehmann Ulrich, Celikkaya Gülhan, Hasemeier Britta, Länger Florian, Kreipe Hans
Institute of Pathology, Department of Pathology, Medizinische Hochschule Hannover, D-30625 Hannover, Germany.
Cancer Res. 2002 Nov 15;62(22):6634-8.
Expression of death-associated protein (DAP) kinase, a proapoptotic serine/threonine protein kinase, is frequently lost in human tumors. In a study of 134 primary breast cancer specimens hypermethylation of the DAP kinase gene was found in 13% of cases. A highly significant difference (P < 0.001) of DAP kinase inactivation was observed between invasive lobular cancer (n = 19) and invasive ductal cancer (n = 85; 53% versus 9%, respectively). Hypermethylation correlated with loss of RNA expression, estrogen receptor positivity (P < 0.01), and the absence of p53 overexpression (P < 0.01). In contrast to invasive lobular cancer, the in situ-growing precursor lesion lacked epigenetic modification of the DAP kinase promotor by aberrant methylation indicating a potential role in tumor progression. Unlike the DAP kinase gene, hypermethylation of the cyclin D2 and RASSF1A genes did not correlate with a particular histological subtype or to invasiveness [corrected]. We conclude that different histological subtypes of breast cancer may not only differ concerning specific chromosomal abnormalities and DNA mutations but also with regard to epigenetic inactivation patterns.
死亡相关蛋白（DAP）激酶是一种促凋亡的丝氨酸/苏氨酸蛋白激酶，其表达在人类肿瘤中常常缺失。在一项对134份原发性乳腺癌标本的研究中，发现13%的病例存在DAP激酶基因的高甲基化。浸润性小叶癌（n = 19）和浸润性导管癌（n = 85；分别为53%和9%）之间观察到DAP激酶失活存在高度显著差异（P < 0.001）。高甲基化与RNA表达缺失、雌激素受体阳性（P < 0.01）以及p53过表达缺失（P < 0.01）相关。与浸润性小叶癌不同，原位生长的前体病变未出现因异常甲基化导致的DAP激酶启动子表观遗传修饰，表明其在肿瘤进展中可能发挥作用。与DAP激酶基因不同，细胞周期蛋白D2和RASSF1A基因的高甲基化与特定的组织学亚型或侵袭性无关[校正后]。我们得出结论，乳腺癌的不同组织学亚型不仅在特定染色体异常和DNA突变方面存在差异，而且在表观遗传失活模式方面也存在差异。
