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Mutation signatures in oesophageal adenocarcinoma to direct therapy

▸ Secrier M, Li X, de Silva N, et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 2016;48:1131–41.

Recent next-generation sequencing studies have revealed few common mutated driver genes in patients with oesophageal adenocarcinoma (OAC), particularly those with a known history of Barrett's oesophagus. Genomic instability is a feature of these cancers, and altogether these data paint a picture of tremendous genetic heterogeneity, making it difficult to develop new therapeutic strategies. Here, a comprehensive analysis of copy number changes versus mutations was performed by whole-genome sequencing in 129 patients with OAC. The results were compatible with previous studies that showed a great deal of intrapatient genetic heterogeneity and that chromosomal changes were more prevalent than mutations. No obvious identifiers of cancer subtypes were initially found. However, an interesting observation was made when correlating receptor tyrosine kinase (RTK) copy number changes. Nearly all OAC cases showed amplifications suggesting RTK inhibitors might be a potential therapeutic avenue in this cancer. To search for OAC mutation signatures ‘hidden’ in the high mutation burden, the authors used a previously published non-negative matrix factorisation method—where a mutational signature is built-up from the sequence context of each mutation: there are a possible six classes of base pair substitutions and recording the 5′ and 3′ base of each substitution generates 96 possible mutations that can be identified, and these have been shown to reflect natural history of the cancer such as ageing, ultraviolet exposure and smoking. OAC specimens revealed six signatures that were significant in three: (1) enrichment for BReast CAncer susceptibility gene (BRCA) signature, (2) high mutation signature and (3) an ageing signature. Importantly, these have therapeutic relevance. This report describes for the first time identifiable subtypes of OAC. The authors were able to procure cell lines that …

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