Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, SE 751 85, Sweden.
BMC Genomics. 2013 Mar 12;14:165. doi: 10.1186/1471-2164-14-165.
Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing.
We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology.
Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.
在乳腺癌基因组中经常观察到染色体重排的形式，如缺失、插入、倒位和易位，其中一些重排可能在肿瘤发生中起关键作用。为了鉴定新的体细胞染色体重排，我们通过长插入片段配对大规模平行测序确定了 15 个激素受体阴性乳腺癌肿瘤的基因组结构。
我们鉴定并验证了 40 个体细胞结构改变，包括基因 DDX10 和 SKA3 之间的反复融合以及涉及 EPHA5 基因的易位。其他重排影响涉及表观遗传调控、有丝分裂和信号转导途径的基因，强调了它们在乳腺癌发生中的潜在作用。五个候选基因（DDX10、SKA3、EPHA5、CLTC 和 TNIK）的 RNA 干扰介导的抑制导致乳腺癌细胞生长受到抑制。此外，乳腺癌细胞中 DDX10 的下调导致凋亡核形态的频率增加。
使用全基因组配对测序和 RNA 干扰测定，我们在乳腺癌基因组中发现了一些新的基因重排，并确定 DDX10、SKA3、EPHA5、CLTC 和 TNIK 作为潜在的癌症基因，对乳腺癌细胞的生长和增殖有影响。
