Abstract：
Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In order to address the extent to which chromosomal structural rearrangement breakpoints correlate with recurrent DNA double-strand breaks (DSBs), we simultaneously mapped chromosome structural variation breakpoints (using whole-genome DNA-seq) and spontaneous DSB formation (using Break-seq) in the estrogen receptor (ER)-positive breast cancer cell line MCF-7 and a non-cancer control breast epithelium cell line MCF-10A. We identified concurrent DSBs and structural variation breakpoints almost exclusively in the pericentromeric region of chromosome 16q in MCF-7 cells. We fine-tuned the identification of copy number variation breakpoints on 16q. In addition, we detected recurrent DSBs that occurred in both MCF-7 and MCF-10A. We propose a model for DSB-driven chromosome rearrangements that lead to the translocation of 16q, likely with 10q, and the eventual 16q loss that does not involve the pericentromere of 16q. We present evidence from RNA-seq data that select genes, including SHCBP1, ORC6, and MYLK3, which are immediately downstream from the 16q pericentromere, show heightened expression in MCF-7 cell line compared to the control. Data published by The Cancer Genome Atlas show that all three genes have increased expression in breast tumor samples. We found that SHCBP1 and ORC6 are both strong poor prognosis and treatment outcome markers in the ER-positive breast cancer cohort. We suggest that these genes are potential oncogenes for breast cancer progression. The search for tumor suppressor loss that accompanies the 16q loss ought to be augmented by the identification of potential oncogenes that gained expression during chromosomal rearrangements.
摘要：
癌症基因组的特征是小规模体细胞突变以及大规模染色体缺失的积累。扩增,和复杂的结构重组。该特征至少部分取决于癌细胞经历反复染色体断裂的能力。为了解决染色体结构重排断点与复发性DNA双链断裂（DSB）相关的程度，我们同时在雌激素受体(ER)阳性乳腺癌细胞系MCF-7和非癌对照乳腺上皮细胞系MCF-10A中定位染色体结构变异断点(使用全基因组DNA-seq)和自发DSB形成(使用Break-seq).我们在MCF-7细胞中几乎仅在染色体16q的着丝粒区域中确定了并发的DSB和结构变异断点。我们微调了16q上拷贝数变异断点的鉴定。此外,我们检测到MCF-7和MCF-10A中发生的复发DSB。我们提出了一个DSB驱动的染色体重排模型，该模型导致16q的易位，可能是10q，以及最终的16q损失，不涉及16q的着丝粒。我们从RNA-seq数据中提供了选择基因的证据，包括SHCBP1，ORC6和MYLK3，它们紧接在16q着丝粒的下游，与对照相比,在MCF-7细胞系中的表达增加。癌症基因组图谱发表的数据显示，所有这三种基因在乳腺肿瘤样品中的表达都增加。我们发现SHCBP1和ORC6在ER阳性乳腺癌队列中都是强烈的不良预后和治疗结果标志物。我们认为这些基因是乳腺癌进展的潜在癌基因。应通过鉴定在染色体重排过程中获得表达的潜在癌基因来增强对伴随16q损失的肿瘤抑制物损失的搜索。
