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推断无法获得的癌前病变的早期遗传进展

原文发布日期：2023-04-20

英文摘要：

摘要翻译：

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推断无法获得的癌前病变的早期遗传进展

Inferring early genetic progression in cancers with unobtainable premalignant disease

原文发布日期：2023-04-20

英文摘要：

Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV–) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV+ HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.

摘要翻译：

通过分析半癌前组织，我们识别了在几种癌症中由体细胞事件引发侵袭性肿瘤的典型顺序。对于其他癌症，由于无法获得半癌前组织，遗传进展尚不清楚。在这里，我们展示了如何从原发肿瘤的exome测序推断遗传进展。我们的计算方法PhylogicNDT成功再现了实验确定的人 papillomavirus（HPV）-阴性头颈部鳞状细胞癌（HNSCC）的遗传进展。随后，我们评估了HPV阳性 HNSCC，由于缺乏半癌前组织，其遗传进展尚不明确，并揭示了其以前未知的早期驱动力。我们将体细胞驱动突变和 HPV 积分的发生时间估计值转换为基于诊断年前的时间，根据具有时钟样突变特征的时间序列模式。我们发现，aneuploidy（染色体数目变异）发生的时间与肿瘤内遗传多样性的增加以及整体生存率的缩短有关。我们的方法可以确定那些由于无法获得半癌前组织而未知早期驱动因素的癌症的遗传进展，从而支持开发实验模型和早期检测、拦截及预后的方法。