Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA.
Department of Pathology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA.
Gynecol Oncol. 2018 Feb;148(2):281-285. doi: 10.1016/j.ygyno.2017.12.004. Epub 2017 Dec 9.
In ovarian carcinoma, mutations in homologous recombination DNA repair (HRR) genes, including BRCA1 and RAD51C, are associated with increased survival and specific clinical features. Promoter hypermethylation is another mechanism of reducing gene expression. We assessed whether BRCA1 and RAD51C promoter hypermethylation is associated with similar survival and clinical characteristics.
Promoter methylation of BRCA1 and RAD51C was evaluated using methylation-sensitive PCR in 332 primary ovarian carcinomas. Damaging germline and somatic mutations in 16 HRR genes were identified using BROCA sequencing.
BRCA1 methylation was detected in 22 carcinomas (6.6%) and RAD51C methylation in 9 carcinomas (2.7%). These small numbers limited the power to detect differences in survival and platinum sensitivity. Mutations in one or more HRR genes were found in 95 carcinomas (29%). Methylation of BRCA1 or RAD51C was mutually exclusive with mutations in these genes (P=0.001). Patients whose carcinomas had BRCA1 methylation (57.7years±2.5) or BRCA1 mutations (54.1years±1.4) were younger than those without (63.3years±0.8; P=0.029, P<0.0001). BRCA1 methylation and germline BRCA1 mutation were associated with high grade serous (HGS) histology (P=0.045, P=0.001). BRCA1 mutations were associated with increased sensitivity to platinum chemotherapy while BRCA1 methylation was not (P=0.034, P=0.803). Unlike HRR mutations, methylation was not associated with improved overall survival compared to cases without methylation or mutation.
Patients with BRCA1-methylated carcinomas share clinical characteristics with patients with BRCA1-mutated carcinomas including younger age and predominantly HGS histology. However, unlike mutation, RAD51C and BRCA1 methylation were not associated with improved survival or greater sensitivity to platinum chemotherapy.
在卵巢癌中，同源重组 DNA 修复（HRR）基因（包括 BRCA1 和 RAD51C）的突变与生存时间延长和特定的临床特征相关。启动子超甲基化是另一种降低基因表达的机制。我们评估了 BRCA1 和 RAD51C 启动子超甲基化是否与类似的生存和临床特征相关。
使用甲基敏感 PCR 评估 332 例原发性卵巢癌中 BRCA1 和 RAD51C 的启动子甲基化。使用 BROCA 测序鉴定 16 个 HRR 基因中的有害种系和体细胞突变。
在 22 例（6.6%）癌中检测到 BRCA1 甲基化，在 9 例（2.7%）癌中检测到 RAD51C 甲基化。这些小数量限制了检测生存和铂类敏感性差异的能力。在 95 例（29%）癌中发现一个或多个 HRR 基因突变。BRCA1 或 RAD51C 的甲基化与这些基因的突变是相互排斥的（P=0.001）。BRCA1 甲基化（57.7 岁±2.5）或 BRCA1 突变（54.1 岁±1.4）的患者比无 BRCA1 甲基化（63.3 岁±0.8）或无 BRCA1 突变的患者年轻（P=0.029，P<0.0001）。BRCA1 甲基化和种系 BRCA1 突变与高级别浆液性（HGS）组织学相关（P=0.045，P=0.001）。BRCA1 突变与对铂类化疗的敏感性增加相关，而 BRCA1 甲基化则不然（P=0.034，P=0.803）。与 HRR 突变不同，与无甲基化或突变的病例相比，甲基化与总生存时间的改善无关。
BRCA1 甲基化癌患者与 BRCA1 突变癌患者具有相似的临床特征，包括年龄较小和主要为 HGS 组织学。然而，与突变不同，RAD51C 和 BRCA1 甲基化与生存时间改善或对铂类化疗的敏感性增加无关。
