Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
Research Department of Cancer Biology and Medical Genomics Laboratory, UCL Cancer Institute, University College London, London, UK.
Nat Med. 2019 Mar;25(3):517-525. doi: 10.1038/s41591-018-0323-0. Epub 2019 Jan 21.
The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer.
在癌症表现之前，细胞中发生的分子改变在很大程度上是未知的。肺癌原位（CIS）病变是鳞状细胞癌的侵袭前前体。尽管在显微镜下相同，但它们的未来处于平衡状态，一半进展为浸润性癌，一半消退或保持静止。这种临床观察的细胞学基础尚不清楚。在这里，我们对具有纵向监测的侵袭前疾病的独特患者队列中的 CIS 进行了基因组、转录组和表观基因组图谱分析。预测建模以惊人的准确性识别出哪些病变会进展。我们在广泛的异质性背景下发现了进展特异性的甲基化变化，以及强烈的染色体不稳定性特征。我们观察到了具有癌症特征的突变和拷贝数变化，并追踪了它们的出现，为早期癌变提供了一个窗口。我们预计，对癌症前体生物学的这种新认识将改善早期检测，减少过度治疗，并促进针对肺癌早期克隆事件的预防性治疗。
