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致死性转移性前列腺癌的进化史。

The evolutionary history of lethal metastatic prostate cancer.

作者信息

Gundem Gunes, Van Loo Peter, Kremeyer Barbara, Alexandrov Ludmil B, Tubio Jose M C, Papaemmanuil Elli, Brewer Daniel S, Kallio Heini M L, Högnäs Gunilla, Annala Matti, Kivinummi Kati, Goody Victoria, Latimer Calli, O'Meara Sarah, Dawson Kevin J, Isaacs William, Emmert-Buck Michael R, Nykter Matti, Foster Christopher, Kote-Jarai Zsofia, Easton Douglas, Whitaker Hayley C, Neal David E, Cooper Colin S, Eeles Rosalind A, Visakorpi Tapio, Campbell Peter J, McDermott Ultan, Wedge David C, Bova G Steven

机构信息

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.

Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium.

出版信息

Nature. 2015 Apr 16;520(7547):353-357. doi: 10.1038/nature14347. Epub 2015 Apr 1.

Abstract

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

摘要

癌症源自一个持续的达尔文进化过程,常常导致单个原发性肿瘤内出现多个相互竞争的亚克隆。这一进化过程最终导致转移灶的形成,而转移是90%的癌症相关死亡的原因。然而,尽管其在临床上具有重要意义,但对于癌细胞扩散至远处器官的调控机制却知之甚少。虽然每个转移灶都源自单个肿瘤细胞这一假说通常得到支持,但最近利用癌症小鼠模型进行的研究表明,存在多个亚克隆的多克隆播种及亚克隆间的合作。在此,我们寻求人类恶性肿瘤中多克隆播种存在的确凿证据,并在去势转移性前列腺癌的背景下确定不同转移灶之间的克隆关系。通过全基因组测序,我们对10例患者前列腺肿瘤产生的多个转移灶进行了特征分析。对亚克隆结构的综合分析以前所未有的细节揭示了转移扩散的模式。发现转移灶之间的扩散很常见,要么是通过子代转移灶的从头单克隆播种,要么在5例中是通过多个肿瘤克隆在转移部位之间的转移。影响肿瘤抑制基因的病变通常是单个事件,而涉及雄激素受体信号传导的基因中的突变通常在不同转移灶中涉及多个趋同事件。我们的结果详细阐明了转移扩散的复杂模式,并进一步加深了我们对前列腺癌去势抵抗治疗发展的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b7f/4413032/18f82db79b77/emss-62345-f0005.jpg

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