原发性和转移性实体瘤的泛癌全基因组比较

SCI 1 June 2023

Pan-cancer whole-genome comparison of primary and metastatic solid tumours

 (Nature, IF: 69.504)

Martínez-Jiménez F, Movasati A, Brunner SR, Nguyen L, Priestley P, Cuppen E, Van Hoeck A. Pan-cancer whole-genome comparison of primary and metastatic solid tumours. Nature. 2023 May 10. doi: 10.1038/s41586-023-06054-z. Epub ahead of print. PMID: 37165194.

Corresponding author: Edwin Cuppen, e-mail: e.cuppen@hartwigmedicalfoundation.nl

Abstract 概要

Metastatic cancer remains an almost inevitably lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours and late-stage treated metastatic tumours using a harmonized pan-cancer analysis (or reanalysis) of two unpaired primary and metastatic cohorts of 7,108 whole-genome-sequenced tumours. Metastatic tumours in general have a lower intratumour heterogeneity and a conserved karyotype, displaying only a modest increase in mutations, although frequencies of structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions of mutational footprints of endogenous (for example, SBS1 and APOBEC) and exogenous mutational processes (for example, platinum treatment) are present. The majority of cancer types had either moderate genomic differences (for example, lung adenocarcinoma) or highly consistent genomic portraits (for example, ovarian serous carcinoma) when comparing early-stage and late-stage disease. Breast, prostate, thyroid and kidney renal clear cell carcinomas and pancreatic neuroendocrine tumours are clear exceptions to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. Exposure to treatment further scars the tumour genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcase the potential of pan-cancer whole-genome analysis to identify distinctive features of late-stage tumours and provide a valuable resource to further investigate the biological basis of cancer and resistance to therapies.

转移性癌症仍然是一种几乎不可避免的致命疾病。因此，更好地了解疾病进展和对治疗的反应仍然至关重要。在这里，我们通过对7108个全基因组序列肿瘤的两个未匹配原发性和转移性队列进行统一的泛癌分析（或再分析），来描述早期未治疗原发性肿瘤和晚期治疗后转移性肿瘤之间的基因组差异。转移性肿瘤通常具有较低的瘤内异质性和保守的核型，尽管结构变异的频率总体上较高，但突变仅适度增加。此外，高度可变的肿瘤特异性促进内源性（例如SBS1和APOBEC）和外源性突变过程（例如铂类药物治疗）的突变足迹。在比较早期和晚期疾病时，大多数癌症类型具有中度基因组差异（例如，肺腺癌），或高度一致的基因组图谱（例如，卵巢浆液性癌）。乳腺癌、前列腺癌、甲状腺癌和肾透明细胞癌以及胰腺神经内分泌肿瘤显然是这一规则的例外，它们在晚期表现出基因组特征的广泛转变。暴露于治疗进一步损伤了肿瘤基因组，并引入了一个进化瓶颈，在大约一半的接受治疗的患者中出现了已知的耐药驱动基因选择。我们的数据显示了泛癌全基因组分析的潜力，可以确定晚期肿瘤的独特特征，并为进一步研究癌症的生物学基础和治疗耐药性提供了宝贵的资源。

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