DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer
DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer
复制标题
BRCA1主要转录起始位点直接上游区域的DNA甲基化是高级别浆液性卵巢癌患者的独立有利预后因素
DOI：
10.1016/j.ygyno.2022.10.008
复制
发表时间：
2022
影响因子：
4.7
通讯作者：
Ushijima Toshikazu
中科院分区：
文献类型：
--
作者：
Ebata Takahiro;Yamashita Satoshi;Takeshima Hideyuki;Yoshida Hiroshi;Kawata Yoshiko;Kino Nao;Yasugi Toshiharu;Terao Yasuhisa;Yonemori Kan;Kato Tomoyasu;Ushijima Toshikazu
目的建立一种定量评价BRCA1主要转录起始位点（tss）上游区域DNA甲基化水平的方法，探讨该区域甲基化是否为高级别浆液性卵巢癌患者新辅助化疗后预后的影响因素。方法对2011 - 2018年晚期高级别浆液性卵巢癌新辅助化疗后的92例FFPE样本进行突变和甲基化分析。通过焦磷酸测序和DNA甲基化芯片检测DNA甲基化水平。通过Kaplan-Meier分析评估甲基化水平（或突变）与无进展生存期之间的关系。结果鉴定出主要brca1转录本及其tss上游的CpG位点，并建立了焦磷酸测序方法。在17/79（21.5%）、17/92（18.5%）和1/92（1.1%）高级别严重卵巢癌样本中检测到brca1甲基化、brca1 /2突变和arad51突变。在单因素分析中，brca1甲基化和无肿瘤残留与无进展生存相关（brca1甲基化：P= 0.025，无肿瘤残留：P= 0.0026）。多因素分析显示，brca1甲基化（P= 0.038, HR = 0.47, 95% CI: 0.21-0.96）和无肿瘤残留（P= 0.012, HR = 0.49, 95% CI: 0.28-0.85）是显著的预后有利因素。结论建立了一种定量估计brca1tsss上游直接区甲基化水平的方法。区域甲基化是高级别浆液性卵巢癌患者预后的独立有利因素。
ObjectiveTo establish a quantitative method to evaluate the DNA methylation level of an immediate upstream region of major BRCA1 transcriptional start sites (TSSs), and to investigate whether methylation of the region is a prognostic factor in high-grade serous ovarian cancer patients after neoadjuvant chemotherapy.MethodsNinety-two FFPE samples of advanced high-grade serous ovarian cancers after neoadjuvant chemotherapy between 2011 and 2018 were used for mutation and methylation analysis. DNA methylation levels were assessed by pyrosequencing and DNA methylation microarray. An association between methylation level (or a mutation) and progression-free survival was assessed by Kaplan-Meier analysis.ResultMajorBRCA1transcripts and CpG sites immediately upstream of their TSSs were identified, and a pyrosequencing method was developed.BRCA1methylation,BRCA1/2mutations, and aRAD51Cmutation were detected in 17/79 (21.5%), 17/92 (18.5%), and 1/92 (1.1%) high-grade serious ovarian cancer samples. In univariate analysis,BRCA1methylation and no residual tumor were associated with progression-free survival (BRCA1methylation:P= 0.025, no residual tumor:P= 0.0026). Multivariate analysis showed that bothBRCA1methylation (P= 0.038, HR = 0.47, 95% CI: 0.21–0.96) and no residual tumor (P= 0.012, HR = 0.49, 95% CI: 0.28–0.85) were significant favorable prognostic factors.ConclusionA quantitative method to estimate the methylation level of the immediate upstream region of majorBRCA1TSSs was established. Methylation of the region of was an independent favorable prognostic factor in high-grade serous ovarian cancer patients.