Hilton Jeffrey L, Geisler John P, Rathe Jennifer A, Hattermann-Zogg Melanie A, DeYoung Barry, Buller Richard E
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA.
J Natl Cancer Inst. 2002 Sep 18;94(18):1396-406. doi: 10.1093/jnci/94.18.1396.
Although BRCA1 and BRCA2 play important roles in hereditary ovarian cancers, the extent of their role in sporadic ovarian cancers and their mechanisms of inactivation are not yet well understood. Our goal was to characterize BRCA2 mutations and mRNA expression in a group of ovarian tumors previously evaluated for BRCA1 mutations and mRNA expression.
The tumors of 92 unrelated women with "ovarian" cancer (i.e., ovarian, peritoneal, or fallopian tube cancer) were screened for BRCA2 null mutations using a protein truncation test. Methylation-specific polymerase chain reaction (PCR) was used to examine the BRCA2 promoter for hypermethylation in tumors that did not express BRCA2 mRNA. All statistical tests were two-sided.
Nine tumors had a germline (n = 5) or somatic (n = 4) BRCA2 mutation; each was associated with loss of heterozygosity. All of the somatic (1445delC, E880X, 4286del8, and 5783delT) and one of the germline (5984ins4) mutations were unique to this study. One tumor had somatic mutations in both BRCA1 and BRCA2. Two tumors are, to our knowledge, the first cases of germline BRCA2-associated peritoneal cancer. Twelve additional tumors lacked detectable BRCA2 mRNA, but the BRCA2 promoter was hypermethylated in only one of them, suggesting that other mechanisms effect transcriptional silencing of BRCA2. Tumors lacking BRCA1 mRNA were more likely to lack BRCA2 mRNA than tumors expressing BRCA1 mRNA (P<.001). Overall, 82% (95% confidence interval [CI] = 74% to 90%) of the tumors contained alterations in BRCA1, BRCA2, or both genes. Of 41 informative tumors with some alteration in BRCA2, 36 also had an alteration in BRCA1. The frequency, but not the mechanism, of BRCA1 or BRCA2 dysfunction in ovarian cancer was independent of family history.
Multiple mechanisms cause nearly universal dysfunction of BRCA1 and/or BRCA2 in hereditary and sporadic ovarian carcinoma. Ovarian cancers with BRCA2 dysfunction often have simultaneous BRCA1 dysfunction.
尽管BRCA1和BRCA2在遗传性卵巢癌中发挥重要作用，但其在散发性卵巢癌中的作用程度及其失活机制尚未完全明确。我们的目标是对一组先前已评估过BRCA1突变和mRNA表达的卵巢肿瘤中的BRCA2突变及mRNA表达进行特征分析。
采用蛋白质截短试验对92名患“卵巢”癌（即卵巢癌、腹膜癌或输卵管癌）的不相关女性的肿瘤进行BRCA2无效突变筛查。对于不表达BRCA2 mRNA的肿瘤，采用甲基化特异性聚合酶链反应（PCR）检测BRCA2启动子的高甲基化情况。所有统计检验均为双侧检验。
9个肿瘤存在种系（n = 5）或体细胞（n = 4）BRCA2突变；每个突变均与杂合性缺失相关。所有体细胞突变（1445delC、E880X、4286del8和5783delT）及其中一个种系突变（5984ins4）均为本研究所特有。1个肿瘤同时存在BRCA1和BRCA2的体细胞突变。据我们所知，2个肿瘤是首例种系BRCA2相关的腹膜癌病例。另有12个肿瘤未检测到BRCA2 mRNA，但其中仅1个肿瘤的BRCA2启动子发生高甲基化，提示存在其他机制影响BRCA2的转录沉默。与表达BRCA1 mRNA的肿瘤相比，缺乏BRCA1 mRNA的肿瘤更可能缺乏BRCA2 mRNA（P<0.001）。总体而言，82%（95%置信区间[CI]=74%至90%）的肿瘤存在BRCA1、BRCA2或二者基因的改变。在41个BRCA2有某种改变的信息充分的肿瘤中，36个同时也有BRCA1的改变。卵巢癌中BRCA1或BRCA2功能障碍的频率与家族史无关，但机制相关。
多种机制导致遗传性和散发性卵巢癌中BRCA1和/或BRCA2几乎普遍功能障碍。存在BRCA2功能障碍的卵巢癌通常同时存在BRCA1功能障碍。
