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Τρίτη 23 Μαΐου 2017

Development and validation of an ultra-deep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer

Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy. <p>Experimental Design: We developed a highly sensitive ultra-deep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared to molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.</p> <p>Results: In a study of 55 patients with advanced cancer, the ultra-deep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P=0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P=0.02), and  compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P=0.03).</p> <p>Conclusions: Ultra-deep NGS assay has good sensitivity compared to conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF.



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