CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma.
CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma.
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DOI：
10.1371/journal.pgen.1004216
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Yen L
中科院分区：
文献类型：
--
作者：
Kannan K;Coarfa C;Rajapakshe K;Hawkins SM;Matzuk MM;Milosavljevic A;Yen L
卵巢癌是女性癌症死亡的第五大原因。几乎70%的卵巢癌死亡是由于高级别浆液性亚型，通常只有在转移后才能检测到。高级别浆液性癌的特征进一步复杂化的显着异质性和基因组的不稳定性，这种癌症显示。除了在TP 53中的突变，这是常见的许多癌症，高度复发的重组事件，具体到这种癌症尚未确定。使用7个患者样本的高通量转录组测序结合DNA、RNA和蛋白质水平的实验验证，我们鉴定了癌症特异性和染色体间融合基因CDKN 2D-WDFY 2，其在60个高级别浆液性癌样本中以20%的频率出现，但在非癌性卵巢和输卵管样本中不存在。这是迄今为止在高级别浆液性癌中鉴定的最常见的重组事件，这意味着在这种高度异质性的癌症中存在主要的细胞谱系。此外，在已建立的高级别浆液性细胞系OV-90中也检测到相同的融合转录本。在患者肿瘤中的CDKN 2D的内含子1和WDFY 2的内含子2中鉴定出基因组断裂点，提供了这是融合基因的直接证据。亲本基因CDKN 2D是一种细胞周期调节剂，也参与DNA修复，而WDFY 2已知调节AKT与其底物的相互作用。克隆的融合构建体的转染导致野生型CDKN 2D和野生型WDFY 2蛋白表达的丧失，以及推测在CDKN 2D启动子控制下的短WDFY 2蛋白同种型的获得。短WDFY 2蛋白在转染细胞中的表达似乎改变了已知在肿瘤发生中起作用的PI 3 K/AKT通路。CDKN 2D-WDFY 2融合蛋白可能是一个重要的分子标记，以了解和分类的亚系异质性高级别浆液性卵巢癌。高级别浆液性癌（HG-SC）是女性中观察到的最常见的卵巢癌亚型。由于缺乏有效的早期筛查工具，这种卵巢癌亚型通常在晚期被检测到。由染色体易位引起的复发性癌症特异性基因融合有可能作为有效的筛选工具以及治疗靶点。在这里，我们确定CDKN 2D-WDFY 2作为癌症特异性融合基因存在于20%的HG-SC肿瘤中，这是迄今为止在这种高度异质性疾病中发现的最常见的基因重组事件。我们还提供了证据表明，这种融合的表达可能会影响PI 3 K/AKT通路，这对癌症进展很重要。因此，CDKN 2D-WDFY 2可以很好地代表一个主要的细胞谱系，对异质性卵巢癌的检测和分类很重要，并可以深入了解这种致命疾病的潜在机制。这一点至关重要，因为卵巢癌每年在全球造成140，200名女性死亡，目前很少有卵巢癌特异性分子改变可用于靶向和筛查。
Ovarian cancer is the fifth leading cause of cancer death in women. Almost 70% of ovarian cancer deaths are due to the high-grade serous subtype, which is typically detected only after it has metastasized. Characterization of high-grade serous cancer is further complicated by the significant heterogeneity and genome instability displayed by this cancer. Other than mutations in TP53, which is common to many cancers, highly recurrent recombinant events specific to this cancer have yet to be identified. Using high-throughput transcriptome sequencing of seven patient samples combined with experimental validation at DNA, RNA and protein levels, we identified a cancer-specific and inter-chromosomal fusion gene CDKN2D-WDFY2 that occurs at a frequency of 20% among sixty high-grade serous cancer samples but is absent in non-cancerous ovary and fallopian tube samples. This is the most frequent recombinant event identified so far in high-grade serous cancer implying a major cellular lineage in this highly heterogeneous cancer. In addition, the same fusion transcript was also detected in OV-90, an established high-grade serous type cell line. The genomic breakpoint was identified in intron 1 of CDKN2D and intron 2 of WDFY2 in patient tumor, providing direct evidence that this is a fusion gene. The parental gene, CDKN2D, is a cell-cycle modulator that is also involved in DNA repair, while WDFY2 is known to modulate AKT interactions with its substrates. Transfection of cloned fusion construct led to loss of wildtype CDKN2D and wildtype WDFY2 protein expression, and a gain of a short WDFY2 protein isoform that is presumably under the control of the CDKN2D promoter. The expression of short WDFY2 protein in transfected cells appears to alter the PI3K/AKT pathway that is known to play a role in oncogenesis. CDKN2D-WDFY2 fusion could be an important molecular signature for understanding and classifying sub-lineages among heterogeneous high-grade serous ovarian carcinomas. High-grade serous carcinoma (HG-SC) is the most common subtype of ovarian cancer observed in women. This subtype of ovarian cancer is typically detected at advanced stages due to lack of effective early screening tools. Recurrent cancer-specific gene fusions resulting from chromosomal translocations have the potential to serve as effective screening tools as well as therapeutic targets. Here we identified CDKN2D-WDFY2 as a cancer-specific fusion gene present in 20% of HG-SC tumors, by far the most frequent gene recombinant event found in this highly heterogeneous disease. We also presented evidence that the expression of this fusion may affect the PI3K/AKT pathway that is important for cancer progression. Thus CDKN2D-WDFY2 could very well represent a major cellular lineage important for detecting and classifying heterogeneous ovarian carcinomas, and could provide insight into the underlying mechanism of this deadly disease. This is critical, given that ovarian cancer kills 140,200 women worldwide each year, and few ovarian cancer-specific molecular alterations are currently available for targeting and screening.
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影响因子：
5.8
作者：
Neeley, E. Shannon;Kornblau, Steven M.;Baggerly, Keith A.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0508832103
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