Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma
Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma
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DOI：
10.1038/modpathol.2011.183
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发表时间：
2012-04-01
期刊：
影响因子：
7.5
通讯作者：
Levine, Douglas A.
中科院分区：
文献类型：
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作者：
Soslow, Robert A.;Han, Guangming;Levine, Douglas A.
本研究假设卵巢癌的某些常见形态学特征与BRCA 1和BRCA 2缺陷相关。我们选择了43例在纪念斯隆-凯特琳癌症中心诊断的高级别浆液性癌，作为癌症基因组图谱试点项目的一部分进行研究。除了12例随机选择的非家族性BRCA无关病例外，还纳入了所有31例伴有BRCA 1或BRCA 2异常的纪念斯隆-凯特琳癌症中心病例（n=43）。检查载玻片以评估肿瘤结构、有丝分裂指数、肿瘤浸润淋巴细胞（TIL）、核多形性、坏死和输卵管上皮受累。比较BRCA 1相关病例（BRCA 1生殖系突变，n=4，BRCA 1体细胞突变，n=6，BRCA 1启动子甲基化，n=13）与非相关病例（n=12），发现形态学差异具有统计学意义。BRCA 1相关的高级别浆液性癌具有更常见的实体、假子宫内膜样和移行细胞癌样形态（SET特征）（P=0.0045），更高的有丝分裂指数（P=0.012），更多的TIL（P=0.034），以及地理状或粉刺状坏死（P=0.034）。BRCA 2相关病例（生殖细胞突变，n=4和体细胞突变，n = 4）倾向于显示SET特征，但它们在TIL和坏死方面相对缺乏。结合肿瘤结构、坏死和有丝分裂指数或TlL的两种算法将显示3个特征中的2个（BRCA 1相关）的病例与显示3个特征中的0个（BRCA无关; P=0.0016和P=0.0033）的病例分开。包括9个BRCA 1种系突变体和14个缺乏BRCA 1和BRCA 2种系突变的高级别浆液性癌对照的测试集用于验证算法，特别强调检测BRCA 1种系突变病例的能力。结合SET特征、坏死和有丝分裂指数的算法获得了最佳结果（P=0.0072;灵敏度为1.0（95%CI，0.66-1.0）;特异性为0.57（95% CI，0.29-0.82）;阳性预测值为0.60（95% CI，0.32-0.84），阴性预测值为1.0（95% CI，0.63-1.0））。这些初步数据表明，在高级别浆液性癌的形态和基因型之间的潜在的强关联。Modern Pathology（2012）25，625-636; doi：10.1038/modpathol.2011.183; 2011年12月23日在线发表
This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinomalike morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012),more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n = 4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TlLs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% Cl, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas. Modern Pathology (2012) 25, 625-636; doi:10.1038/modpathol.2011.183; published online 23 December 2011