在高级别浆液性卵巢癌中，BRCA1免疫组化检测种系、体细胞和表观遗传BRCA1缺失的性能。
The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.
作者信息
Meisel J L, Hyman D M, Garg K, Zhou Q, Dao F, Bisogna M, Gao J, Schultz N D, Grisham R N, Phillips M, Iasonos A, Kauff N D, Levine D A, Soslow R A, Spriggs D R
机构信息
Gynecologic Medical Oncology Service.
Gynecologic Medical Oncology Service; Developmental Therapeutics, Department of Medicine; Weill Cornell Medical College, New York, USA.
出版信息
Ann Oncol. 2014 Dec;25(12):2372-2378. doi: 10.1093/annonc/mdu461. Epub 2014 Oct 3.
BACKGROUND
BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms.
PATIENTS AND METHODS
Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups.
RESULTS
Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92).
CONCLUSIONS
BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.
背景
BRCA1表达可通过多种机制丧失，包括种系或体细胞突变以及启动子高甲基化。鉴于BRCA1缺失作为高级别浆液性卵巢癌预测和预后生物标志物的潜在重要性，我们试图评估BRCA1免疫组织化学（IHC）在筛查因种系、体细胞和表观遗传机制导致的BRCA1缺失中的效用。
患者与方法
确定之前接受过种系BRCA1检测的晚期高级别浆液性卵巢癌患者。对每个肿瘤样本进行BRCA1染色，并由两名对BRCA状态不知情的病理学家独立进行评估。BRCA1 IHC异常且种系检测为野生型的肿瘤，进一步评估体细胞BRCA1突变和启动子高甲基化情况。采用McNemar检验确定BRCA1 IHC与种系BRCA1突变以及通过任何机制导致的BRCA1缺失之间的关联。采用Kaplan-Meier方法估计总生存期（OS），并使用对数秩检验评估组间差异。
结果
两名病理学家对BRCA IHC解读的评分者间可靠性非常好（kappa系数0.865，P = 0.16；McNemar检验）。36%（48/135）的病例BRCA1 IHC异常。与种系BRCA1状态相比，BRCA1 IHC具有较高的阴性预测值（95.4%），但阳性预测值较低（PPV，52.1%）。当将启动子高甲基化和体细胞突变作为BRCA1缺失的替代方法考虑在内时，PPV升至87.5%。种系BRCA1突变患者的五年OS率为49.6% [95%置信区间（CI）26.3%至69.3%]，种系BRCA1野生型且IHC异常患者为50.4%（95% CI 27.5%至69.5%），种系BRCA1野生型且IHC正常患者为52.1%（95% CI 38.4%至64.2%）（P = 0.92）。
结论
BRCA1 IHC解读是检测BRCA1缺失的种系、体细胞或表观遗传机制的高度可重复且准确的方法。这些结果支持进一步开发BRCA1 IHC作为高级别浆液性卵巢癌中BRCA1缺失的潜在生物标志物。
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