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Identification of gene fusion transcripts by transcriptome sequencing in BRCA1 -mutated breast cancers and cell lines

机译：通过转录组测序鉴定BRCA1突变的乳腺癌和细胞系中的基因融合转录本

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Background Gene fusions arising from chromosomal translocations have been implicated in cancer. However, the role of gene fusions in BRCA1 -related breast cancers is not well understood. Mutations in BRCA1 are associated with an increased risk for breast cancer (up to 80% lifetime risk) and ovarian cancer (up to 50%). We sought to identify putative gene fusions in the transcriptomes of these cancers using high-throughput RNA sequencing (RNA-Seq). Methods We used Illumina sequencing technology to sequence the transcriptomes of five BRCA1 -mutated breast cancer cell lines, three BRCA1 -mutated primary tumors, two secretory breast cancer primary tumors and one non-tumorigenic breast epithelial cell line. Using a bioinformatics approach, our initial attempt at discovering putative gene fusions relied on analyzing single-end reads and identifying reads that aligned across exons of two different genes. Subsequently, latter samples were sequenced with paired-end reads and at longer cycles (producing longer reads). We then refined our approach by identifying misaligned paired reads, which may flank a putative gene fusion junction. Results As a proof of concept, we were able to identify two previously characterized gene fusions in our samples using both single-end and paired-end approaches. In addition, we identified three novel in-frame fusions, but none were recurrent. Two of the candidates, WWC1-ADRBK2 in HCC3153 cell line and ADNP-C20orf132 in a primary tumor, were confirmed by Sanger sequencing and RT-PCR. RNA-Seq expression profiling of these two fusions showed a distinct overexpression of the 3' partner genes, suggesting that its expression may be under the control of the 5' partner gene's regulatory elements. Conclusions In this study, we used both single-end and paired-end sequencing strategies to discover gene fusions in breast cancer transcriptomes with BRCA1 mutations. We found that the use of paired-end reads is an effective tool for transcriptome profiling of gene fusions. Our findings suggest that while gene fusions are present in some BRCA1 -mutated breast cancers, they are infrequent and not recurrent. However, private fusions may still be valuable as potential patient-specific biomarkers for diagnosis and treatment.
机译：背景技术由染色体易位引起的基因融合涉及癌症。但是，基因融合在BRCA1相关乳腺癌中的作用尚不清楚。 BRCA1中的突变与乳腺癌（最高80％的终生风险）和卵巢癌（最高50％）的风险增加相关。我们试图使用高通量RNA测序（RNA-Seq）在这些癌症的转录组中鉴定推定的基因融合体。方法我们使用Illumina测序技术对5个BRCA1突变的乳腺癌细胞系，3个BRCA1突变的原发肿瘤，2个分泌性乳腺癌原发性肿瘤和1个非致瘤性乳腺癌上皮细胞系的转录组进行测序。使用生物信息学方法，我们发现推定的基因融合体的最初尝试依赖于分析单端读取并鉴定跨两个不同基因外显子排列的读取。随后，将后面的样本与配对末端的读数进行测序，并以更长的周期进行（产生更长的读数）。然后，我们通过识别错位的配对读段来完善我们的方法，该配对读段可能位于假定的基因融合连接的侧面。结果作为概念验证，我们能够使用单端和配对方法在样品中鉴定出两种先前表征的基因融合体。此外，我们确定了三种新颖的框架内融合，但没有一种是复发性的。通过Sanger测序和RT-PCR证实了两个候选基因，即HCC3153细胞系中的WWC1-ADRBK2和原发性肿瘤中的ADNP-C20orf132。这两种融合的RNA-Seq表达图谱显示3'伴侣基因有明显的过表达，表明其表达可能受5'伴侣基因的调控元件控制。结论在这项研究中，我们使用单端和双端测序策略来发现具有BRCA1突变的乳腺癌转录组中的基因融合。我们发现，使用配对末端读取是基因融合转录组分析的有效工具。我们的研究结果表明，尽管基因融合存在于某些BRCA1突变的乳腺癌中，但并不常见，也不会复发。但是，私人融合可能仍然有价值，可以作为潜在的患者特异性生物标志物进行诊断和治疗。

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