Abstract
AbstractBackgroundHepatocellular carcinoma (HCC) incidence is increasing worldwide and prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Circulating cell‐free DNA of tumour origin (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We determined the utility of ctDNA as a prognostic biomarker of survival in HCC.MethodsPlasma cell‐free DNA and matched germline DNA were isolated from patients with HCC (n = 51) and cirrhosis (n = 10). Targeted, multiplex PCR ultra‐deep sequencing was performed using a liver cancer‐specific primer panel for genes ALB, AMPH, APC, ARID1A, ARID2, ATM, AXIN1, BAZ2B, BRAF, CSMD3, CTNNB1, DSE, ERBB2, HNF1A, IGFR2, IGSF10, KEAP1, MET, TP53, UBR3, USP25, ZIC3 and ZNF226. Associations between mutations in ctDNA and overall survival were analysed using Cox proportional hazards modelling.Results114 putative mutations (70 unique) in were detected in plasma ctDNA in 35 of 51 patients with HCC (69%). On univariable analysis, CSMD3 gene mutations were associated with shorter overall survival (Logrank HR 3.18, 95% CI 1.14‐8.86, P = .027). The median survival time was 15.5 months (IQR 7.77‐16.5 months) in patients with CSMD3 mutations compared with the median survival of 26.5 months (IQR 16.93‐46.07 months) in patients without CSMD3 mutations. Other factors associated with overall survival were advanced BCLC stage (HR 16.52, 95% CI 2.22‐122.94, P = .006) and Child‐Pugh Class (CPC HR 7.98, 95% CI 2.31‐27.61, P = .001). Cox proportional hazards modelling showed mutations in CSMD3 remained a significant independent risk for shorter overall survival in HCC when adjusted for age, BCLC stage and Child‐Pugh class (HR 4.91, 95% CI 1.60‐15.02, P = .005).ConclusionDetection of CSMD3 mutations in plasma ctDNA is associated with reduced overall survival in HCC patients, adjusted for potential confounding factors.
Highlights
Hepatocellular carcinoma (HCC) is the seventh most common cancer and fourth most common cause of cancer-related death worldwide[1] and incidence continues to increase in parallel with the global epidemics of viral hepatitis[2] and non-alcoholic fatty liver disease.[3]
Circulating cell-free DNA is an exciting potential alternative to tissue biopsy that may overcome the need for tumour biopsy. cfDNA is released through apoptosis and necrosis from both healthy and malignant cells into the blood stream.[9,10]
The aim of this study was to determine whether the detection of mutations in well-established carcinogenic driver genes in ctDNA are associated with overall survival in HCC patients
Summary
Hepatocellular carcinoma (HCC) is the seventh most common cancer and fourth most common cause of cancer-related death worldwide[1] and incidence continues to increase in parallel with the global epidemics of viral hepatitis[2] and non-alcoholic fatty liver disease.[3]. CfDNA is released through apoptosis and necrosis from both healthy and malignant cells into the blood stream.[9,10] Tumour-derived cfDNA (ctDNA) can be distinguished from wild-type cfDNA by identification of somatic alterations present in the tumour of interest, but not in matched somatic tissue.[9] ctDNA quantification and the presence of genetic and epigenetic variants within ctDNA are attractive biomarkers in cancer,[9,11] facilitating dynamic assessment of genetic mutations before, during and after treatment without the need for repeated tumour biopsies.[10,12,13]. Cox proportional hazards modelling showed mutations in CSMD3 remained a significant independent risk for shorter overall survival in HCC when adjusted for age, BCLC stage and Child-Pugh class (HR 4.91, 95% CI 1.60-15.02, P = .005). Conclusion: Detection of CSMD3 mutations in plasma ctDNA is associated with reduced overall survival in HCC patients, adjusted for potential confounding factors
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