The clonal relationships between pre-cancer and cancer revealed by ultra-deep sequencing. prego clonality study

Previous work studying the clonal evolution of cancer has inferred the earliest mutations by comparisons of multiple patients or examination of variant allele frequencies. We performed ultra-deep sequencing of selected variants and copy number analysis from multiple pre-invasive lesions, primary tumors and metastatic samples from five oral squamous cell carcinoma patients, some with multiple primary tumors presenting either synchronously or metachronously. This allowed the earliest genomic events to be directly observed. We used a novel approach to analyze the clonal network of mutations across each patient’s disease, revealing the relationships between pre-cancer and cancer and, ultimately, the diversity of mechanisms of tumor initiation, spread and metastasis.

既往针对癌症克隆进化的研究，多通过比对多例患者的基因组数据，或分析变异等位基因频率（variant allele frequencies）来推断最早出现的突变事件。本研究对5例口腔鳞状细胞癌（oral squamous cell carcinoma）患者的多份浸润前病变（pre-invasive lesions）、原发肿瘤及转移样本中的选定变异位点开展超深度测序（ultra-deep sequencing），并进行拷贝数分析（copy number analysis）；其中部分患者存在多灶性原发肿瘤，且表现为同步或异时性发病。这一实验设计使得研究人员能够直接观测到最早发生的基因组事件。本研究采用全新的分析方法，对每位患者病程中的突变克隆网络（clonal network of mutations）进行解析，揭示了癌前病变与恶性肿瘤之间的演化关系，并最终阐明了肿瘤发生、扩散及转移的多种潜在机制。