Jazaeri Amir A, Yee Cindy J, Sotiriou Christos, Brantley Kelly R, Boyd Jeff, Liu Edison T
Division of Clinical Sciences of the National Cancer Institute, Gaithersburg, MD,USA.
J Natl Cancer Inst. 2002 Jul 3;94(13):990-1000. doi: 10.1093/jnci/94.13.990.
Germline mutations in BRCA1 and BRCA2 are responsible for 5%-10% of epithelial ovarian cancers, but the molecular pathways affected by these mutations are unknown. We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors.
Tumor samples from 61 patients with pathologically confirmed epithelial ovarian adenocarcinoma with matched clinicopathologic features were studied, including 18 with BRCA1 founder mutations, 16 with BRCA2 founder mutations, and 27 without either founder mutation (termed sporadic cancers). The cDNA microarrays contained 7651 sequence-verified features. Gene expression data were analyzed with a modified two-sided F test, with P<.0001 considered statistically significant. The expression level of six genes was also studied with reverse transcription-polymerase chain reaction.
The greatest contrast in gene expression was observed between tumors with BRCA1 mutations and those with BRCA2 mutations; 110 genes showed statistically significantly different expression levels (P<.0001). This group of genes could segregate sporadic tumors into two subgroups, "BRCA1-like" and "BRCA2-like," suggesting that BRCA1-related and BRCA2-related pathways are also involved in sporadic ovarian cancers. Fifty-three genes were differentially expressed between tumors with BRCA1 mutations and sporadic tumors; six of the 53 mapped to Xp11.23 and were expressed at higher levels in tumors with BRCA1 mutations than in sporadic tumors. Compared with the immortalized ovarian surface epithelial cells used as reference, several interferon-inducible genes were overexpressed in the majority of tumors with a BRCA mutation and in sporadic tumors.
Mutations in BRCA1 and BRCA2 may lead to carcinogenesis through distinct molecular pathways that also appear to be involved in sporadic cancers. Sporadic carcinogenic pathways may result from epigenetic aberrations of BRCA1 and BRCA2 or their downstream effectors.
BRCA1和BRCA2的种系突变导致5%-10%的上皮性卵巢癌，但这些突变所影响的分子途径尚不清楚。我们使用互补DNA（cDNA）微阵列来比较与BRCA1或BRCA2突变相关的卵巢癌中的基因表达模式与散发性上皮性卵巢癌中的基因表达模式，并确定遗传性和散发性肿瘤共有的模式。
研究了61例经病理证实的具有匹配临床病理特征的上皮性卵巢腺癌患者的肿瘤样本，其中18例有BRCA1始祖突变，16例有BRCA2始祖突变，27例无任何始祖突变（称为散发性癌症）。cDNA微阵列包含7651个经序列验证的特征。基因表达数据采用改良的双侧F检验进行分析，P<0.0001被认为具有统计学意义。还采用逆转录-聚合酶链反应研究了六个基因的表达水平。
在有BRCA1突变的肿瘤和有BRCA2突变的肿瘤之间观察到最大的基因表达差异；110个基因显示出统计学上显著不同的表达水平（P<0.0001）。这组基因可将散发性肿瘤分为两个亚组，即“BRCA1样”和“BRCA2样”，这表明与BRCA1相关和与BRCA2相关的途径也参与散发性卵巢癌。在有BRCA1突变的肿瘤和散发性肿瘤之间有53个基因表达差异；这53个基因中的6个定位于Xp11.23，在有BRCA1突变的肿瘤中的表达水平高于散发性肿瘤。与用作对照的永生化卵巢表面上皮细胞相比，几种干扰素诱导基因在大多数有BRCA突变的肿瘤和散发性肿瘤中过表达。
BRCA1和BRCA2的突变可能通过不同的分子途径导致致癌作用，这些途径似乎也参与散发性癌症。散发性致癌途径可能源于BRCA1和BRCA2或其下游效应物的表观遗传畸变。
