Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Illumina Cambridge, Granta Park, Cambridge, UK.
Genome Med. 2021 Feb 25;13(1):33. doi: 10.1186/s13073-021-00852-8.
Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3' transcriptome analysis would give new insights into colorectal cancer.
Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3' RNA-seq.
Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy.
Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.
临床级全基因组测序（cWGS）由于其覆盖范围广泛且不存在基因组区域偏向性，因此有可能成为临床常规的标准。结直肠癌的治疗模式具有挑战性，超过 40%的患者在诊断时已经发生转移。我们假设 cWGS 与 3' 转录组分析相结合，将为结直肠癌提供新的见解。
患者接受无 PCR 全基因组测序和使用标准化流程进行的比对和变异调用，以输出 SNV、indels、SV 和 CNAs。通过使用 3' RNA-seq，可以更深入地了解突变特征和肿瘤生物学。
总共研究了 54 名患者。驱动分析确定 Wnt 通路基因 APC 是结直肠癌中唯一一致突变的驱动基因。PI3K/mTOR 通路的改变如先前在 CRC 中观察到的那样。多个私有 CNAs、SV 和基因融合是单个肿瘤所特有的。约 30%的患者肿瘤突变负担（TMB）> 10 个突变/Mb DNA，提示适合免疫治疗。
临床全基因组测序为鉴定可能对靶向药物敏感的私有基因组变异提供了潜在途径，并为患者提供了新的靶向治疗选择。
