Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
BMC Cancer. 2017 Sep 11;17(1):642. doi: 10.1186/s12885-017-3625-6.
A fusion gene is a hybrid gene consisting of parts from two previously independent genes. Chromosomal rearrangements leading to gene breakage are frequent in high-grade serous ovarian carcinomas and have been reported as a common mechanism for inactivating tumor suppressor genes. However, no fusion genes have been repeatedly reported to be recurrent driver events in ovarian carcinogenesis. We combined genomic and transcriptomic information to identify novel fusion gene candidates and aberrantly expressed genes in ovarian carcinomas.
Examined were 19 previously karyotyped ovarian carcinomas (18 of the serous histotype and one undifferentiated). First, karyotypic aberrations were compared to fusion gene candidates identified by RNA sequencing (RNA-seq). In addition, we used exon-level gene expression microarrays as a screening tool to identify aberrantly expressed genes possibly involved in gene fusion events, and compared the findings to the RNA-seq data.
We found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19-translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3' end of DPP9 corresponding to the breakpoints identified by RNA-seq. For the exon-level expression analysis, candidate fusion partner genes were ranked according to deviating expression compared to the median of the sample set. The results were collated with data obtained from the RNA-seq analysis. Several fusion candidates were identified, among them TMEM123-MMP27, ZBTB46-WFDC13, and PLXNB1-PRKAR2A, all of which led to stronger expression of the 3' genes. In view of our previous findings of nonrandom rearrangements of chromosome 19 in this cancer type, particular emphasis was given to changes of this chromosome and a DDA1-FAM129C fusion event was identified.
We have identified novel fusion gene candidates in high-grade serous ovarian carcinoma. DPP9 was involved in two different fusion transcripts that both resulted in deregulated expression of the 3' end of the transcript and thus possible loss of the active domains in the DPP9 protein. The identified rearrangements might play a role in tumorigenesis or tumor progression.
融合基因是由两个先前独立的基因的部分组成的杂合基因。导致基因断裂的染色体重排在高级别浆液性卵巢癌中很常见，并且已被报道为失活肿瘤抑制基因的常见机制。然而，在卵巢癌发生中，没有融合基因被反复报道为反复出现的驱动事件。我们结合基因组和转录组信息来鉴定卵巢癌中的新融合基因候选物和异常表达基因。
研究了 19 个先前进行核型分析的卵巢癌（18 个浆液性组织学类型和 1 个未分化）。首先，将核型异常与通过 RNA 测序（RNA-seq）鉴定的融合基因候选物进行比较。此外，我们使用外显子水平的基因表达微阵列作为筛选工具来鉴定可能涉及基因融合事件的异常表达基因，并将这些发现与 RNA-seq 数据进行比较。
我们在一个显示 11;19 易位的肿瘤中发现了一个 DPP9-PPP6R3 融合转录本。另一个肿瘤的 DPP9 与 PLIN3 发生重排。这两种重排均与 RNA-seq 确定的断点处的 DPP9 3'末端的表达减少有关。对于外显子水平的表达分析，候选融合伴侣基因根据与样本集中位数相比的差异表达进行排序。结果与从 RNA-seq 分析获得的数据进行了整理。鉴定出了几个融合候选物，其中包括 TMEM123-MMP27、ZBTB46-WFDC13 和 PLXNB1-PRKAR2A，它们都导致了 3'基因的更强表达。鉴于我们之前在这种癌症类型中发现的染色体 19 的非随机重排，特别强调了该染色体的变化，并鉴定出了一个 DDA1-FAM129C 融合事件。
我们在高级别浆液性卵巢癌中鉴定出了新的融合基因候选物。DPP9 参与了两个不同的融合转录本，这两个转录本都导致了转录本 3'末端的失调表达，从而可能导致 DPP9 蛋白的活性结构域丧失。鉴定出的重排可能在肿瘤发生或肿瘤进展中发挥作用。
