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Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand

1
Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
2
Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
3
Division of Bioinformatics and Data Management for Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
4
Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
5
Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
*
Authors to whom correspondence should be addressed.
Academic Editor: Amedeo Columbano
Cancers 2021, 13(9), 2229; https://doi.org/10.3390/cancers13092229
Received: 25 March 2021 / Revised: 28 April 2021 / Accepted: 29 April 2021 / Published: 6 May 2021
Liquid biopsy for cell-free DNA (cfDNA) is a non-invasive technique to characterize the genetic profile of a tumor. Despite being a valuable tool, there is no mutational profile of cfDNA from hepatocellular carcinoma (HCC) in patients from Thailand, where HCC is prevalent. The present study aimed to demonstrate the utility of using whole-exome sequencing of cfDNA to define the somatic mutation profiles of HCC in Thai patients who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients than in chronic hepatitis patients. Single nucleotide variations were present in somatic genes in cfDNA, including in ZNF814, HRNR, ZNF492, ADAMTS12, FLG, OBSCN, TP53, and TTN. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival. These findings indicate that the mutational profiles of cfDNA reflected those of HCC tissue, and cfDNA could serve as a useful biomarker for diagnosis and prognosis in HCC patients.
Cell-free DNA (cfDNA) has been used as a non-invasive biomarker for detecting cancer-specific mutations. However, the mutational profile of cfDNA in Thai patients with hepatocellular carcinoma (HCC) has not been investigated. Here, we demonstrated the utility of using whole-exome sequencing (WES) of cfDNA to define the somatic mutation profiles of HCC in Thai patients. The comprehensive profile of cfDNA was determined with WES to identify variants in matched cfDNA and germline DNA from 30 HCC patients in Thailand who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients compared with chronic hepatitis patients (p-value < 0.001). Single nucleotide variants were present in somatic genes in cfDNA, including in ZNF814 (27%), HRNR (20%), ZNF492 (20%), ADAMTS12 (17%), FLG (17%), OBSCN (17%), TP53 (17%), and TTN (17%). These same mutations were matched to HCC mutation data from The Cancer Genome Atlas (TCGA) and a previous Thai HCC study. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival in HCC patients (hazard ratio = 1.60, p-value = 0.0196). These findings indicate that the mutational profile of cfDNA accurately reflected that of HCC tissue and suggest that cfDNA could serve as a useful biomarker for diagnosis and prognosis in Thai HCC patients. In addition, we demonstrated the use of the pocket-sized sequencer of Oxford Nanopore Technology to detect copy-number variants in HCC tissues that could be applied for onsite clinical detection/monitoring of HCC. View Full-Text
Keywords: hepatocellular carcinoma; cell-free DNA; whole-exome sequencing; biomarker; Thailand; Oxford Nanopore Technologies; copy-number variants hepatocellular carcinoma; cell-free DNA; whole-exome sequencing; biomarker; Thailand; Oxford Nanopore Technologies; copy-number variants
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MDPI and ACS Style

Kunadirek, P.; Chuaypen, N.; Jenjaroenpun, P.; Wongsurawat, T.; Pinjaroen, N.; Sirichindakul, P.; Nookaew, I.; Tangkijvanich, P. Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand. Cancers 2021, 13, 2229. https://doi.org/10.3390/cancers13092229

AMA Style

Kunadirek P, Chuaypen N, Jenjaroenpun P, Wongsurawat T, Pinjaroen N, Sirichindakul P, Nookaew I, Tangkijvanich P. Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand. Cancers. 2021; 13(9):2229. https://doi.org/10.3390/cancers13092229

Chicago/Turabian Style

Kunadirek, Pattapon, Natthaya Chuaypen, Piroon Jenjaroenpun, Thidathip Wongsurawat, Nutcha Pinjaroen, Pongserath Sirichindakul, Intawat Nookaew, and Pisit Tangkijvanich. 2021. "Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand" Cancers 13, no. 9: 2229. https://doi.org/10.3390/cancers13092229

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