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荷兰乌得勒支大学Edwin Cuppen研究团队完成原发性和转移性实体肿瘤的泛癌症全基因组比较。相关论文于2023年5月10日在线发表在《自然》杂志上。

通过对7108个全基因组测序肿瘤的两个未配对的原发和转移队列进行统一的泛癌症分析（或重新分析），研究人员描述了早期未治疗的原发肿瘤和后期治疗的转移性肿瘤之间的基因组差异。转移性肿瘤一般具有较低的瘤内异质性和保守的核型，只显示出突变的适度增加，尽管结构性变异的频率总体上有所提高。此外，内源性（如SBS1和APOBEC）和外源性突变过程（如顺铂治疗）的突变足迹对肿瘤的贡献高度不同。

在比较早期和晚期疾病时，大多数癌症类型都有中等程度的基因组差异（例如肺腺癌）或高度一致的基因组特征（例如卵巢浆液性癌）。乳腺、前列腺、甲状腺和肾脏透明细胞癌以及胰腺神经内分泌肿瘤是明显的例外，在晚期显示出其基因组图谱的广泛转变。暴露在治疗中会进一步破坏肿瘤基因组，并引入一个演化瓶颈，在大约一半的治疗患者中选择已知的抗治疗驱动因素。

这些数据展示了泛癌症全基因组分析的潜力，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对治疗的抵抗提供了宝贵的资源。

据了解，转移性癌症仍然是一种几乎不可避免的致命性疾病。因此，更好地了解疾病的发展和对治疗的反应仍然是最重要的。

附：英文原文

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

Author: Martnez-Jimnez, Francisco, Movasati, Ali, Brunner, Sascha Remy, Nguyen, Luan, Priestley, Peter, Cuppen, Edwin, Van Hoeck, Arne

Issue&Volume: 2023-05-10

Abstract: Metastatic cancer remains an almost inevitably lethal disease1,2,3. 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 primary4 and metastatic5 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.

DOI: 10.1038/s41586-023-06054-z

Source: https://www.nature.com/articles/s41586-023-06054-z

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