Massively‐parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary

作者：Richard W. Tothill, Jason Li, Linda Mileshkin, Kenneth Doig, Terence Siganakis, Prue A. Cowin, ANDREW P. FELLOWES, Timothy J. Semple, Stephen B. Fox, Keith A. Byron, Adam Kowalczyk, David Morgan Thomas, Penelope E. Schofield, David D.L. Bowtell · 发表于：The Journal of Pathology · 年份：2013 · DOI：10.1002/path.4251 · 被引用次数：113 · 研究领域：Cancer Diagnosis and Treatment、Head and Neck Cancer Studies、Oral Health Pathology and Treatment

The clinical management of patients with cancer of unknown primary (CUP) is hampered by the absence of a definitive site of origin. We explored the utility of massively-parallel (next-generation) sequencing for the diagnosis of a primary site of origin and for the identification of novel treatment options. DNA enrichment by hybridization capture of 701 genes of clinical and/or biological importance, followed by massively-parallel sequencing, was performed on 16 CUP patients who had defied attempts to identify a likely site of origin. We obtained high quality data from both fresh-frozen and formalin-fixed, paraffin-embedded samples, demonstrating accessibility to routine diagnostic material. DNA copy-number obtained by massively-parallel sequencing was comparable to that obtained using oligonucleotide microarrays or quantitatively hybridized fluorescently tagged oligonucleotides. Sequencing to an average depth of 458-fold enabled detection of somatically acquired single nucleotide mutations, insertions, deletions and copy-number changes, and measurement of allelic frequency. Common cancer-causing mutations were found in all cancers. Mutation profiling revealed therapeutic gene targets and pathways in 12/16 cases, providing novel treatment options. The presence of driver mutations that are enriched in certain known tumour types, together with mutational signatures indicative of exposure to sunlight or smoking, added to clinical, pathological, and molecular indicators of likely ...