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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. |