BACKGROUND:It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements. RESULTS:We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing-55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer-in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator. CONCLUSIONS:This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.

译文

背景:最近发现,常见的上皮癌(如乳腺癌)具有与白血病相关的融合基因。在代表性的乳腺癌细胞系ZR-75-30中,我们通过分析基因组重排搜索了融合基因。
结果:我们首先通过分子细胞遗传学方法,结合阵列绘画和阵列CGH,分析了ZR-75-30基因组的重排,分辨率约为10kb。然后,我们将该图与通过配对末端测序确定的基因组连接进行了比较。通过阵列涂装和阵列CGH发现的大多数断点是在配对末端测序中鉴定的,其中55%的未扩增断点和97%的扩增断点(因为它们由更多的序列读数表示)。通过此分析,我们确定了9个表达的融合基因:APPBP2-PHF20L1,BCAS3-HOXB9,COL14A1-SKAP1,TAOK1-PCGF2,TIAM1-NRIP1,TIMM23-ARHGAP32,TRPS1-LASP1,USP32-CCDC49和ZMYM4-OPRD1我们还确定了BCAS3-ERBB2,DDX5-DEPDC6 / DEPTOR和PLEC1-ENPP2等人所描述的另外三个表达的融合基因的基因组连接。在这12个表达的融合基因总数中,有9个在共扩增中。由于所用技术的敏感性,我们估计这12个融合基因约为真实总数的三分之二。许多融合似乎可能是驱动程序突变。例如,将PHF20L1,BCAS3,TAOK1,PCGF2和TRPS1融合到其他乳腺癌中。 HOXB9和PHF20L1是融合在其他肿瘤中的基因家族的成员。除ERBB2之外,其他几个基因也与癌症有关,SKAP1是Src的衔接子,DEPTOR调节mTOR通路,而NRIP1是雌激素受体的调节剂。
结论:这是乳腺癌基因组的首次结构分析,该分析将经典的分子细胞遗传学方法与测序相结合。配对末端测序能够检测几乎所有具有足够读取深度的断点。它支持以下观点:基因断裂和基因融合是乳腺癌中重要的突变类别,典型的乳腺癌表达许多融合基因。

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