Boukerroucha Meriem, Josse Claire, Segers Karin, El-Guendi Sonia, Frères Pierre, Jerusalem Guy, Bours Vincent
University of Liège, GIGA-Cancer Research, Human Genetics Unit, Liège, Belgium.
Division of Medical Oncology, Liège University and CHU Sart Tilman Liège, Liège, Belgium.
BMC Cancer. 2015 Mar 26;15:181. doi: 10.1186/s12885-015-1205-1.
Germline mutations in breast cancer susceptibility gene 1 (BRCA1) increase the risk of breast and ovarian cancers. However, no association between BRCA1 germline mutation and glioblastoma malignancy has ever been highlighted. Here we report two cases of BRCA1 mutated patients who developed a glioblastoma multiform (GBM).
Two patients diagnosed with triple negative breast cancer (TNBC) were screened for BRCA1 germline mutation. They both carried a pathogenic mutation introducing a premature STOP codon in the exon 11 of the BRCA1 gene. Few years later, both patients developed a glioblastoma and a second breast cancer. In an attempt to clarify the role played by a mutated BRCA1 allele in the GBM development, we investigated the BRCA1 mRNA and protein expression in breast and glioblastoma tumours for both patients. The promoter methylation status of this gene was also tested by methylation specific PCR as BRCA1 expression is also known to be lost by this mechanism in some sporadic breast cancers.
Our data show that BRCA1 expression is maintained in glioblastoma at the protein and the mRNA levels, suggesting that loss of heterozygosity (LOH) did not occur in these cases. The protein expression is tenfold higher in the glioblastoma of patient 1 than in her first breast carcinoma, and twice higher in patient 2. In agreement with the high protein expression level in the GBM, BRCA1 promoter methylation was not observed in these tumours. In these two cases, despite of a BRCA1 pathogenic germline mutation, the tumour-suppressor protein expression is maintained in GBM, suggesting that the BRCA1 mutation is not instrumental for the GBM development.
乳腺癌易感基因1（BRCA1）的种系突变会增加患乳腺癌和卵巢癌的风险。然而，BRCA1种系突变与胶质母细胞瘤恶性肿瘤之间从未有过关联。在此，我们报告两例发生多形性胶质母细胞瘤（GBM）的BRCA1突变患者。
对两名诊断为三阴性乳腺癌（TNBC）的患者进行BRCA1种系突变筛查。她们都携带一种致病突变，该突变在BRCA1基因的第11外显子中引入了一个过早的终止密码子。几年后，两名患者均发生了胶质母细胞瘤和第二次乳腺癌。为了阐明BRCA1突变等位基因在GBM发生中所起的作用，我们研究了两名患者乳腺癌和胶质母细胞瘤肿瘤中BRCA1的mRNA和蛋白表达。由于已知在一些散发性乳腺癌中该基因的表达也会通过这种机制丧失，因此还通过甲基化特异性PCR检测了该基因的启动子甲基化状态。
我们的数据表明，胶质母细胞瘤中BRCA1的蛋白和mRNA水平表达得以维持，提示这些病例中未发生杂合性缺失（LOH）。患者1的胶质母细胞瘤中蛋白表达比其首次乳腺癌中的高10倍，患者2中则高2倍。与GBM中高蛋白表达水平一致，这些肿瘤中未观察到BRCA1启动子甲基化。在这两个病例中，尽管存在BRCA1致病种系突变，但GBM中肿瘤抑制蛋白表达得以维持，提示BRCA1突变对GBM的发生不起作用。
