乳腺癌中 11q24.1-24.2 区域 LOH11CR2A、PIG8 和 CHEK1 基因的频繁改变：临床和预后意义。
Frequent alterations of LOH11CR2A, PIG8 and CHEK1 genes at chromosomal 11q24.1-24.2 region in breast carcinoma: clinical and prognostic implications.
机构信息
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
出版信息
Mol Oncol. 2011 Oct;5(5):454-64. doi: 10.1016/j.molonc.2011.06.005. Epub 2011 Jul 7.
To understand the importance of frequent deletions at chromosome 11q24.1-24.2 region in breast carcinoma, alterations (deletion/methylation) of the candidate genes LOH11CR2A, ROBO3, ROBO4, HEPACAM, PIG8 and CHEK1 located in this region were analyzed in 106 breast carcinoma samples. Among these genes, LOH11CR2A showed highest frequency of deletion (56%), followed by PIG8 (35%), CHEK1 (31%) and ROBO3/ROBO4/HEPACAM loci (28%). Comparable frequency of promoter methylation (26-35%) was observed for LOH11CR2A, CHEK1 and PIG8. Overall alterations (deletion/methylation) of these genes were in the following order: LOH11CR2A (60%) > PIG8 (46%) > CHEK1 (41%) and showed significant association with each other. Breast carcinoma samples that were estrogen/progesterone receptor negative showed significantly high deletion and overall alterations than estrogen/progesterone receptor positive samples for LOH11CR2A, CHEK1 and PIG8. The methylation and overall alteration of LOH11CR2A were significantly associated with tumor stages in breast carcinoma. However, in early/late onset and estrogen/progesterone receptor positive/negative breast carcinoma, the overall alterations of LOH11CR2A, PIG8 and CHEK1 were differentially associated with advanced stages, tumor grade and lymph node metastasis. Alterations of PIG8 and CHEK1 were significantly associated with poor prognosis in patients with early age of onset of the disease indicating significant prognostic importance. Quantitative mRNA expression analysis detected reduced expression of the genes in the order LOH11CR2A > CHEK1 > PIG8. Immunohistochemical analysis showed reduced protein expression of PIG8 and CHEK1 that was concordant with their molecular alterations. Thus, our study suggests that LOH11CR2A, PIG8 and CHEK1 are candidate tumor suppressor genes associated with breast carcinoma and have significant clinical as well as prognostic importance.
为了理解 11q24.1-24.2 染色体区域频繁缺失在乳腺癌中的重要性，分析了该区域候选基因 LOH11CR2A、ROBO3、ROBO4、HEPACAM、PIG8 和 CHEK1 的改变（缺失/甲基化）在 106 例乳腺癌样本中。在这些基因中，LOH11CR2A 的缺失频率最高（56%），其次是 PIG8（35%）、CHEK1（31%）和 ROBO3/ROBO4/HEPACAM 位点（28%）。LOH11CR2A、CHEK1 和 PIG8 的启动子甲基化频率相当（26-35%）。这些基因的总体改变（缺失/甲基化）的顺序为：LOH11CR2A（60%）>PIG8（46%）>CHEK1（41%），并且彼此之间存在显著关联。雌激素/孕激素受体阴性的乳腺癌样本与雌激素/孕激素受体阳性的样本相比，LOH11CR2A、CHEK1 和 PIG8 的缺失和总体改变明显更高。LOH11CR2A 的甲基化和总体改变与乳腺癌的肿瘤分期显著相关。然而，在早期/晚期发病和雌激素/孕激素受体阳性/阴性的乳腺癌中，LOH11CR2A、PIG8 和 CHEK1 的总体改变与晚期、肿瘤分级和淋巴结转移显著相关。PIG8 和 CHEK1 的改变与疾病早期发病患者的不良预后显著相关，表明其具有重要的预后意义。定量 mRNA 表达分析显示，基因的表达按 LOH11CR2A>CHEK1>PIG8 的顺序降低。免疫组织化学分析显示 PIG8 和 CHEK1 的蛋白表达减少，与它们的分子改变一致。因此，我们的研究表明，LOH11CR2A、PIG8 和 CHEK1 是与乳腺癌相关的候选肿瘤抑制基因，具有重要的临床和预后意义。
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