Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from ‘expensive’ targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development.

This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.

精准诊断是精准医学的两大支柱之一。过去十年的测序工作已将癌症确立为主要由基因驱动的疾病。这一概念得到了针对特定途径的治疗成功的支持，这些途径受到蛋白质编码域中特定驱动突变的干扰，并反映在 FDA 最近批准的三个与组织无关的癌症药物中。此外，越来越多的研究证据表明，通过全基因组测序来询问整个基因组，获得了全球和复杂的基因组畸变，包括基因组非编码区的畸变，也可能反映临床结果。在解决了技术、后勤、财务和道德挑战之后，国家倡议现在旨在将临床全基因组测序引入现实世界的诊断，作为一种合理且具有潜在成本效益的癌症反应预测工具，并确定将从“昂贵”靶向治疗和临床试验招募中受益最大的患者。然而，到目前为止，还没有对全基因组测序在临床试验中对具有明确临床结果的统一治疗患者的临床效用进行系统和前瞻性评估。这种方法还将极大地促进新的预测性生物标志物的发现和验证，最终减少临床试验的规模和持续时间以及药物开发的成本。

这份手稿是三篇系列手稿中的第三篇，旨在回顾和批判性地评估临床全基因组测序在实体瘤和血液恶性肿瘤中的潜力和挑战。