A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma
Labgaa I (1,2), Villacorta-Martin C (1), D'Avola D (1,3), Craig AJ (1), von Felden J (1,4), Martins-Filho SN (1,5,6), Sia D (1), Stueck A (7,8), Ward SC (7), Fiel MI (7), Mahajan M (9), Tabrizian P (1,10), Thung SN (7), Ang C (11), Friedman SL (1), Llovet JM (1,12,13), Schwartz M (1,10), Villanueva A (14,15).
(1) Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
(2) Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland.
(3) Liver Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Clinica Universidad de Navarra, Pamplona, Spain.
(4) I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
(5) Department of Pathology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
(6) Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
(7) Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA.
(8) Department of Pathology, Dalhousie University, Halifax, NS, Canada.
(9) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
(10) Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, USA.
(11) Department of Medicine, Icahn School of Medicine at Mount Sinai, Division of Hematology and Medical Oncology, New York, USA.
(12) Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, CIBEREHD, Hospital Clinic, Universitat de Barcelona, Catalonia, Spain.
(13) Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
(14) Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
(15) Department of Medicine, Icahn School of Medicine at Mount Sinai, Division of Hematology and Medical Oncology, New York, USA.
Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce.
This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples.
We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500× coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1).
This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream.
This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.
CITATION Oncogene. 2018 Apr 9. doi: 10.1038/s41388-018-0206-3