Next generation mapping reveals novel large genomic rearrangements in prostate cancer.
Next generation mapping reveals novel large genomic rearrangements in prostate cancer.
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DOI：
10.18632/oncotarget.15802
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发表时间：
2017-04-04
期刊：
影响因子：
--
通讯作者：
Hayes VM
中科院分区：
文献类型：
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作者：
Jaratlerdsiri W;Chan EKF;Petersen DC;Yang C;Croucher PI;Bornman MSR;Sheth P;Hayes VM
复杂的基因组重排是导致前列腺癌发生的常见分子事件。然而，临床意义尚未完全阐明。使用临床上可行的下一代测序(NGS)技术，检测长度大于1千碱基的大结构变异(SVS)的全范围和亚型是具有挑战性的。下一代测绘(NGM)是一种新的技术，它允许询问单碱基分辨率NGS检测范围之外的百万碱基长度的DNA分子。在这项研究中，我们试图确定使用Irys(Bionano Genology Inc.)的可行性。纳米通道NGM技术生成一个原发性前列腺癌的全基因组图，并与Gleason评分7(4+3)，ETS融合阴性前列腺癌患者的血液匹配。有效的图谱覆盖率为35X，序列覆盖率为60X，肿瘤纯度估计为43%，我们分别鉴定了85个大型体细胞结构重排和6,172个较小的体细胞变体。绝大多数大的SVS(%)，其中73%是插入，不能使用高覆盖率的短读NGS从头开始检测到。然而，对单个NGS读数和NGM衍生候选区域的从头组装支架的引导人工检查允许确认这些大的SVS中的94%，其中超过三分之一的影响基因具有致癌潜力。从这项单患者研究，第一个整合NGS和NGM数据的癌症研究，我们假设在前列腺癌中存在一种新的大型基因组重排谱，这些大型基因组重排可能是肿瘤发生的早期事件，它们有可能提高分类学。
Complex genomic rearrangements are common molecular events driving prostate carcinogenesis. Clinical significance, however, has yet to be fully elucidated. Detecting the full range and subtypes of large structural variants (SVs), greater than one kilobase in length, is challenging using clinically feasible next generation sequencing (NGS) technologies. Next generation mapping (NGM) is a new technology that allows for the interrogation of megabase length DNA molecules outside the detection range of single-base resolution NGS. In this study, we sought to determine the feasibility of using the Irys (Bionano Genomics Inc.) nanochannel NGM technology to generate whole genome maps of a primary prostate tumor and matched blood from a Gleason score 7 (4 + 3), ETS-fusion negative prostate cancer patient. With an effective mapped coverage of 35X and sequence coverage of 60X, and an estimated 43% tumor purity, we identified 85 large somatic structural rearrangements and 6,172 smaller somatic variants, respectively. The vast majority of the large SVs (89%), of which 73% are insertions, were not detectable ab initio using high-coverage short-read NGS. However, guided manual inspection of single NGS reads and de novo assembled scaffolds of NGM-derived candidate regions allowed for confirmation of 94% of these large SVs, with over a third impacting genes with oncogenic potential. From this single-patient study, the first cancer study to integrate NGS and NGM data, we hypothesise that there exists a novel spectrum of large genomic rearrangements in prostate cancer, that these large genomic rearrangements are likely early events in tumorigenesis, and they have potential to enhance taxonomy.