Clinical Utility of Circulating Tumor DNA for Molecular Assessment and Precision Medicine in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low freque
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Clinical Utility of Circulating Tumor DNA for Molecular Assessment and Precision Medicine in Pancreatic Cancer Erina Takai, Yasushi Totoki, Hiromi Nakamura, Mamoru Kato, Tatsuhiro Shibata, and Shinichi Yachida Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect molecular characteristics of tumors, supporting the concept of “liquid biopsy”. We determined the mutational status of KRAS in plasma cfDNA using multiplex droplet digital PCR in 259 patients with PDAC, retrospectively. Furthermore, we constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA in 48 patients who had ≥1 % mutant allele frequencies of KRAS in plasma cfDNA. Droplet digital PCR detected KRAS mutations in plasma cfDNA in 63 of 107 (58.9 %) patients with inoperable tumors. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2 %) examined by cfDNA sequencing. Our two-step approach with plasma cfDNA, combining droplet digital PCR and targeted deep sequencing, is a feasible clinical approach. Assessment of mutations in plasma cfDNA may provide a new diagnostic tool, assisting decisions for optimal therapeutic strategies for PDAC patients.
E. Takai (*) • Y. Totoki • H. Nakamura • M. Kato • S. Yachida Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan e-mail: [email protected] T. Shibata Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan © Springer International Publishing Switzerland 2016 P.B. Gahan et al. (eds.), Circulating Nucleic Acids in Serum and Plasma – CNAPS IX, Advances in Experimental Medicine and Biology 924, DOI 10.1007/978-3-319-42044-8_3
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Keywords
Plasma cfDNA • Targeted deep sequencing • Pancreatic cancer
Introduction Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease and the seventh leading cause of cancer death in the world. Despite a rising incidence worldwide, tools for early detection remain unavailable and the prognosis is poor with a 5-year survival rate limited to approximately 4–7 %. To date, surgery is the only curative treatment for PDAC, but only 15–20 % of patients present with localized, non-metastatic disease. The rapid organ metastasis observed in some patients treated with potentially curative surgery suggests that occult distant metastases may happen very early, negating survival benefit in the subset of operable patients. Whole-genome or exome sequencing analyses have revealed that somatic alterations of the PDAC genome often occur in four genes, namely KRAS, CDKN2A, TP53 and SMAD4 (Waddell et al. 2015; Biankin et al.
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