2023,
Nature Cancer.
DOI:
10.1038/s43018-023-00533-y
Inferring early genetic progression in cancers with unobtainable premalignant disease
Ignaty Leshchiner
, Edmund A. Mroz
, Justin Cha
, Daniel Rosebrock
, Oliver Spiro
, Juliana Bonilla-Velez
, William C. Faquin
, Armida Lefranc-Torres
, Derrick T. Lin
, William A. Michaud
, Gad Getz
, James W. Rocco
Abstract:
Abstract 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.
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2023-04-30 23:21:00
小W:
#paper doi： https://doi.org/10.1038/s43018-023-00533-y inferring early genetic progression in cancers with unobtainable premalignant disease. 作者基于原发肿瘤中亚克隆之间进化关系开发了 PhylogicNDT 方法，使用原发性肿瘤样本的外显子组测序数据来推断癌症的早期遗传进展。作者进行了以下分析，（1）PhylogicNDT 方法能够重现 HPV- HNSCC 的已知遗传进展（Califano 等人的HNSCC经验进展模型） ；（2）PhylogicNDT 方法能够揭示难以获得癌前组织的 HPV+ HNSCC 的癌前遗传进展；（3）比较了 PhylogicNDT 方法 HPV+ 和 HPV– 遗传进展差异；（4）不同驱动事件的进展时间。最后，作者讨论了他们的方法在癌症早期检测、干预和预后评估方面的潜在应用，并指出了一些局限性和未来的改进方向，如考虑肿瘤内空间异质性、增加更多类型的突变、改进突变特征等。
关于HPV+ HNSCC 的 一个观点：根据PhylogicNDT 方法结果提出
，驱动事件可能发生在诊断之前 25-35 年或更早， HPV 整合位点出现在肿瘤发展的早期，并在整个肿瘤发展过程中发生额外的整合，HPV 整合是 HPV+ 癌症发生的主要贡献者。