Introduction: Clinical grade whole genome sequencing (cWGS) has the potential to become 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-prime transcriptome analysis would give new insights into colorectal cancer. Methods: 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 mutational signatures and tumour biology were gained by the use of 3-prime RNAseq. Results: 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 20% of patients had a tumour mutational burden of >10 mutations/Mb of DNA, suggesting suitability for immunotherapy. Conclusions: Clinical whole genome sequencing offers a potential avenue for identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.

中文翻译：

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大肠癌的临床级全基因组测序和3-prime转录组分析证明了大多数患者的靶向改变。

简介：临床级全基因组测序（cWGS）由于其覆盖范围广且对基因组某些区域没有偏见，因此有可能成为诊所内的标准治疗方法。大肠癌呈现出难以治疗的范例，超过40％的患者被诊断出患有转移性疾病。我们假设cWGS结合3-prime转录组分析将为结直肠癌提供新的见解。方法：使用标准化管道对患者进行无PCR的全基因组测序，比对和变异调用，以输出SNV，插入缺失，SV和CNA。通过使用3-prime RNAseq获得了有关突变特征和肿瘤生物学的更多见解。结果：总共研究了54例患者。驱动程序分析确定Wnt通路基因APC是结直肠癌中唯一一致突变的驱动程序。如先前在CRC中观察到的，观察到PI3K / mTOR途径的改变。多个私人CNA，SV和基因融合体是单个肿瘤所独有的。大约20％的患者的肿瘤突变负担大于10个突变/ Mb DNA，这表明适合进行免疫治疗。结论：临床全基因组测序为鉴定私有基因组变异提供了潜在途径，这可能赋予对靶向药物敏感性，并为患者提供靶向治疗的新选择。大约20％的患者具有大于10个突变/ Mb DNA的肿瘤突变负担，表明适用于免疫疗法。结论：临床全基因组测序为鉴定私人基因组变异提供了潜在途径，这可能赋予对靶向药物敏感性，并为患者提供靶向治疗的新选择。大约20％的患者的肿瘤突变负担大于10个突变/ Mb DNA，这表明适合进行免疫治疗。结论：临床全基因组测序为鉴定私人基因组变异提供了潜在途径，这可能赋予对靶向药物敏感性，并为患者提供靶向治疗的新选择。