Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
Fam Cancer. 2009;8(4):339-46. doi: 10.1007/s10689-009-9240-1. Epub 2009 Apr 2.
Mutations in tumor suppressor genes BRCA1 and BRCA2 confer an increased lifetime risk of breast and ovarian cancer. Loss of heterozygosity (LOH) of the wildtype allele has been observed in approximately 80% of tumors from BRCA1 carriers and 70% of tumors from BRCA2 carriers and accounts for the majority of the "second-hits" occurring in BRCA-related tumors. Few sporadic tumors have been reported to have mutations in BRCA. Some sporadic tumors do show LOH of BRCA1 and BRCA2. BRCA1 promoter methylation has also been observed in sporadic ovarian and breast tumors; however, BRCA2 promoter methylation has not been reported in sporadic tumors. The relationship between BRCA LOH and BRCA promoter methylation has not been well characterized in tumors from BRCA germline mutation carriers. The goal of this study was to determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors from mutation carriers that do not show LOH. We studied 38 tumors from BRCA1 carriers and 23 tumors from BRCA2 carriers for LOH. To determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors with germline mutations, we tested 15 tumors lacking LOH and nine tumors with LOH for BRCA1 or BRCA2 promoter methylation. We identified seven BRCA1 tumors and nine BRCA2 tumors lacking LOH. Of these, only one tumor with a BRCA2 mutation showed promoter methylation. These data indicate that promoter methylation is a not a frequent "second-hit" in tumors from BRCA1 or BRCA2 carriers.
肿瘤抑制基因 BRCA1 和 BRCA2 的突变赋予了个体一生中增加罹患乳腺癌和卵巢癌的风险。在约 80%的 BRCA1 携带者的肿瘤和 70%的 BRCA2 携带者的肿瘤中观察到野生型等位基因的杂合性丢失（LOH），并且这是 BRCA 相关肿瘤中大多数“二次打击”的原因。据报道，少数散发性肿瘤存在 BRCA 突变。一些散发性肿瘤确实显示出 BRCA1 和 BRCA2 的 LOH。BRCA1 启动子的甲基化也在散发性卵巢和乳腺癌中观察到；然而，在散发性肿瘤中尚未报道 BRCA2 启动子的甲基化。BRCA 胚系突变携带者的肿瘤中，BRCA LOH 与 BRCA 启动子甲基化之间的关系尚未得到很好的描述。本研究的目的是确定在未显示 LOH 的突变携带者的肿瘤中，BRCA1 和 BRCA2 启动子超甲基化是否作为“二次打击”。我们研究了 38 例 BRCA1 携带者的肿瘤和 23 例 BRCA2 携带者的肿瘤，以检测 LOH。为了确定在存在胚系突变的肿瘤中，BRCA1 和 BRCA2 启动子超甲基化是否作为“二次打击”，我们测试了 15 例缺乏 LOH 的肿瘤和 9 例具有 LOH 的肿瘤的 BRCA1 或 BRCA2 启动子甲基化。我们确定了 7 例 BRCA1 肿瘤和 9 例 BRCA2 肿瘤缺乏 LOH。其中，只有一例具有 BRCA2 突变的肿瘤显示启动子甲基化。这些数据表明，在 BRCA1 或 BRCA2 携带者的肿瘤中，启动子甲基化不是常见的“二次打击”。
