Neurofibromin 1 (NF1) Defects Are Common in Human Ovarian Serous Carcinomas and Co-occur with TP53 Mutations
Neurofibromin 1 (NF1) Defects Are Common in Human Ovarian Serous Carcinomas and Co-occur with TP53 Mutations
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DOI：
10.1593/neo.08784
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Cho, Kathleen R.
中科院分区：
文献类型：
--
作者：
Sangha, Navneet;Wu, Rong;Cho, Kathleen R.
卵巢浆液性癌是卵巢上皮性恶性肿瘤中最常见、最致命的组织学类型。TP 53的突变和Brca 1和/或Brca 2肿瘤抑制蛋白的功能障碍与大部分OSC的分子发病机制有关，但尚未确定其他成熟的肿瘤抑制基因中的频繁体细胞突变。使用36个原发性OSC的DNA拷贝数改变的全基因组筛选，我们鉴定了两个具有明显的NF 1基因纯合缺失的肿瘤。随后，对18个卵巢癌来源的细胞系和41个原代OSC进行了NF 1改变的评价。在18个细胞系中的6个中观察到NF 1蛋白表达显著减少或缺失，并且使用蛋白质截短测试和cDNA和基因组DNA测序，在NF 1表达缺失的6个细胞系中的5个中检测到导致NF 1转录物外显子缺失和/或异常剪接的NF 1突变。类似地，在41个原发性OSC中的9个（22%）中鉴定出包括纯合缺失和剪接突变的NF 1改变。正如预期的那样，NF 1缺陷的肿瘤和细胞系缺乏KRAS或BRAF突变，但基于磷酸化MAPK（原发性肿瘤）的免疫组织化学检测或GTP结合Ras（细胞系）水平升高，显示Ras途径活化。TP 53肿瘤抑制基因在所有记录的NF 1突变的OSC中发生突变，这表明这两种肿瘤抑制蛋白调节的途径通常在卵巢癌浆液性分化的发展中合作。
Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma-derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly reduced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. Similarly, NF1 alterations including homozygous deletions and splicing mutations were identified in 9 (22%) of 41 primary OSCs. As expected, tumors and cell lines with NF1 defects lacked mutations in KRAS or BRAF but showed Ras pathway activation based on immunohistochemical detection of phosphorylated MAPK (primary tumors) or increased levels of GTP-bound Ras (cell lines). The TP53 tumor-suppressor gene was mutated in all OSCs with documented NF1 mutation, suggesting that the pathways regulated by these two tumor-suppressor proteins often cooperate in the development of ovarian carcinomas with serous differentiation.