Schuh Anna, Dreau Helene, Knight Samantha J L, Ridout Kate, Mizani Tuba, Vavoulis Dimitris, Colling Richard, Antoniou Pavlos, Kvikstad Erika M, Pentony Melissa M, Hamblin Angela, Protheroe Andrew, Parton Marina, Shah Ketan A, Orosz Zsolt, Athanasou Nick, Hassan Bass, Flanagan Adrienne M, Ahmed Ahmed, Winter Stuart, Harris Adrian, Tomlinson Ian, Popitsch Niko, Church David, Taylor Jenny C
Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom.
Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.
Cold Spring Harb Mol Case Stud. 2018 Apr 2;4(2). doi: 10.1101/mcs.a002279. Print 2018 Apr.
Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.
新一代测序（NGS）工作已经建立了与癌症发展相关的突变目录。然而，这些信息的临床实用性在很大程度上仍未得到探索。在此，我们展示了英国一项临床全基因组测序（WGS）项目招募的首批8名患者的结果。我们分别使用HiSeq2500 HTv4对新鲜冷冻肿瘤和种系DNA进行了无PCR的WGS，深度分别为75×和30×。对减去种系后的肿瘤变异调用格式（VCF）文件和配对的种系进行了编码区和非编码区的综合分析、种系变异与体细胞获得性变异的整合以及全局突变特征和通路分析。结果被分类为不同等级，并提交给一个多学科肿瘤委员会。WGS结果帮助明确了1例病例中不确定的组织病理学诊断，为2例病例的预后提供了信息或支持，其中1例因此降低了治疗强度，并且在所有8例病例中都指出了潜在的治疗方法。总体而言，与使用常规靶向NGS检测到的6个单核苷酸变异/插入缺失（SNV/indel）相比，使用WGS鉴定出了26个不同的1级潜在可临床应用的发现。这些初步结果证明了WGS在为未来癌症诊断、预后和治疗选择提供信息方面的潜力，并证明有必要在更大规模的癌症患者队列中对WGS的临床实用性进行系统评估。
