Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis.
Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis.
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DOI：
10.1371/journal.pone.0017617
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发表时间：
2011-03-15
期刊：
影响因子：
3.7
通讯作者：
deFazio A
中科院分区：
文献类型：
--
作者：
Emmanuel C;Gava N;Kennedy C;Balleine RL;Sharma R;Wain G;Brand A;Hogg R;Etemadmoghadam D;George J;Australian Ovarian Cancer Study Group;Birrer MJ;Clarke CL;Chenevix-Trench G;Bowtell DD;Harnett PR;deFazio A
导致上皮性卵巢癌的分子事件知之甚少，但排卵激素和大量终身排卵伴随着增殖、细胞凋亡和炎症，增加了风险。我们确定了在发情周期中小鼠卵巢表面上皮细胞中调控的基因，并使用公开可用的数据集分析了这些图谱以识别人类卵巢癌中调控异常的基因。我们鉴定了338个基因，这些基因在发情周期中在小鼠卵巢表面上皮细胞中受到调控，而在卵巢癌中则不受调控。免疫组织化学验证的7个候选者中有6个在浆液性卵巢癌、包涵体囊肿、卵巢表面上皮和输卵管上皮中表达。尽管BIRC5和EZH2在输卵管上皮中高表达，但BIRC5和EZH2在卵巢癌中的表达与卵巢癌一样高，但在卵巢癌中的表达高于卵巢表面上皮和/或包涵体囊肿(EpCAM、EZH2、BIRC5)。我们利用公开可用的数据集对拷贝数、变异和突变进行了计算机分析，确定了在卵巢癌中具有既定作用的基因，以及我们有证据参与卵巢癌的新基因，从而优先考虑那些可能对卵巢癌发展具有重要作用的338个基因。染色体分离是一个重要的过程，在我们列出的338个基因中，有两个(Bub1，NCAPD2)基因过度表达，有证据表明其存在扩增和突变。NUAK2在发情前期卵巢表面上皮细胞中上调，并被预测在卵巢癌中存在驱动突变，在较大的浆液性卵巢癌队列中进行了检测，在这些患者中，NUAK2表达较低的患者总体生存时间较短。总之，定义在排卵过程中正常上皮中被激活的基因，这些基因在癌症中也是异常调节的，已经确定了一些可能与卵巢癌发展有关的途径和新的候选基因。
Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer.
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影响因子：
8
作者：
Donninger, H;Bonome, T;Birrer, MJ
通讯作者：
Birrer, MJ
影响因子：
5.7
作者：
Caldas, H;Jaynes, FO;Altura, RA
通讯作者：
Altura, RA
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
3.8
作者：
Byrne JA;Maleki S;Hardy JR;Gloss BS;Murali R;Scurry JP;Fanayan S;Emmanuel C;Hacker NF;Sutherland RL;Defazio A;O'Brien PM
通讯作者：
O'Brien PM