Jessica Howell1, Stephen R Atkinson2, David J Pinato2, Susanne Knapp3, Caroline Ward2, Rosalba Minisini4, Michela E Burlone4, Monica Leutner4, Mario Pirisi4, Reinhard Büttner5, Shahid A Khan2, Mark Thursz2, Margarete Odenthal5, Rohini Sharma6. 1. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK; Centre for Population Health, Macfarlane-Burnet Institute, 85 Commercial Rd, Melbourne, 3004, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, 55 Victoria Pde, Fitzroy, 3065, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, 85 Commercial Rd, Melbourne 3004, Australia. 2. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK. 3. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK; Department of Women's Cancer, Institute for Women's Health, University College London, 72 Huntley St, London, WC1C6DD, UK. 4. Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy. 5. Institute for Pathology, University Hospital of Cologne and Center of Integrative Oncology, University Clinic of Cologne and Bonn, Kerpener Str. 62, 50924, Cologne, Germany; The Center of Molecular Medicine, The Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany. 6. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK. Electronic address: r.sharma@imperial.ac.uk.
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue. Crown
BACKGROUND:Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue. Crown
Authors: Johann von Felden; Amanda J Craig; Teresa Garcia-Lezana; Ismail Labgaa; Philipp K Haber; Delia D'Avola; Amon Asgharpour; Douglas Dieterich; Antoinette Bonaccorso; Miguel Torres-Martin; Daniela Sia; Max W Sung; Parissa Tabrizian; Myron Schwartz; Josep M Llovet; Augusto Villanueva Journal: Oncogene Date: 2020-10-23 Impact factor: 9.867
Authors: Jingjing Jiao; Jessica I Sanchez; Erika J Thompson; Xizeng Mao; Joseph B McCormick; Susan P Fisher-Hoch; P Andrew Futreal; Jianhua Zhang; Laura Beretta Journal: Int J Mol Sci Date: 2021-07-10 Impact factor: 5.923