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      Investigation of Plasma cell‐free cancer genome chromosomal instability as a tool for targeted minimally invasive biomarkers for primary liver cancer diagnoses


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          To characterize plasma cell‐free cancer genome chromosomal instabilities (CIN) in patients with liver cancer and to evaluate the potential of CIN as minimally invasive biomarkers for primary liver cancer (PLC) diagnoses.

          Experimental Design

          We collected 196 plasma samples from 172 individuals in two cohorts, a discovery cohort of surgery ineligible PLC patients and a validation cohort of hepatectomy patients with pathological disease confirmations. All samples were subjected to HiSeq X10 sequencing followed by a customized bioinformatics workflow Ultrasensitive Chromosome Aneuploidy Detection (UCAD).


          In the discovery cohort, 29 significant copy number changes were identified in plasma from surgery‐ineligible PLC. Twenty‐two (95.7%) surgery‐ineligible liver cancers were identified as harboring copy number changes in at least 1 of 29 segments. Meanwhile 40/41 (97.6%) noncancers harbored no changes. In the validation cohort, 54 (69.4%) surgery‐eligible liver cancers were identified with positive screening, all of which were subsequently confirmed as cancer by pathological examination. Moreover, 26/27 = 96.3% noncancers were identified with negative screening. UCAD‐positive screening was significantly associated with microvascular invasion (OR > 10, 95% CI:[2.53,]), tumor stages B and C (OR = 8.59, 95% CI [1.07, 400]), and tumor size ≥ 3 cm (OR = 5.68, 95% CI [1.43, 28.1]). Furthermore, we collected 29 followed‐up plasma samples from 19 postsurgery patients. Nine (31.0%) postsurgery samples from 6 (31.5%) patients were identified with positive screening. Among them, 3 patients (50.0%) with positive screening were then confirmed as having disease recurrences.


          In addition to AFP, plasma cell‐free DNA sequencing is a useful tool for primary liver cancer diagnoses.


          In addition to AFP, plasma cell‐free DNA sequencing is a useful tool for primary liver cancer diagnoses.

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          Most cited references18

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients.

            The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.
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              TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer.

              Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the major risk factors include chronic infections with the hepatitis B (HBV) or C (HCV) virus, and exposure to dietary aflatoxin B(1) (AFB(1)) or alcohol consumption. Multiple genetic and epigenetic changes are involved in the molecular pathogenesis of HCC, for example, somatic mutations in the p53 tumor suppressor gene (TP53) and the activation of the WNT signal transduction pathway. AFB(1) frequently induces G:C to T:A transversions at the third base in codon 249 of TP53 and cooperates with HBV in causing p53 mutations in HCC. The detection of TP53 mutant DNA in plasma is a biomarker of both AFB(1) exposure and HCC risk. Chronic infection with HBV and HCV viruses, and oxyradical disorders including hemochromatosis, also generate reactive oxygen/nitrogen species that can both damage DNA and mutate cancer-related genes such as TP53. Certain mutant p53 proteins may exhibit a 'gain of oncogenic function'. The p53 biological network is a key responder to this oxidative and nitrosative stress. Depending on the extent of the DNA damage, p53 regulates the transcription of protective antioxidant genes and with extensive DNA damage, transactivates pro-oxidant genes that contribute to apoptosis. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC and the integrated HBx is frequently mutated. Mutant HBx proteins still retain their ability to bind to p53, and attenuate DNA repair and p53-mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology of TP53 mutations during the molecular pathogenesis of HCC.

                Author and article information

                liparislisi@aliyun.com , dingding1700@126.com , yanmeng_ehbh@163.com , hmg301@126.com
                liparislisi@aliyun.com , dingding1700@126.com , yanmeng_ehbh@163.com , hmg301@126.com
                Cancer Med
                Cancer Med
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                27 May 2020
                July 2020
                : 9
                : 14 ( doiID: 10.1002/cam4.v9.14 )
                : 5075-5085
                [ 1 ] Department of Radiotherapy Shanghai Eastern Hepatobiliary Surgery Hospital Shanghai China
                [ 2 ] Department of Hepatic Surgery I(Ward I) Shanghai Eastern Hepatobiliary Surgery Hospital Shanghai China
                [ 3 ] Department of Hepatobiliary and Pancreatic Surgical Oncology Chinese PLA General Hospital and Chinese PLA Medical School Beijing China
                [ 4 ] Prophet Genomics Inc San Jose CA USA
                [ 5 ] Changhai Hospital Second Military Medical University Shanghai China
                Author notes
                [*] [* ] Correspondence

                Nan Li, Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.

                Emails: liparislisi@ 123456aliyun.com

                Yan Meng, Department of Radiotherapy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.

                Email: yanmeng_ehbh@ 123456163.com

                Minggen Hu, Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing 100853, China.

                Email: hmg301@ 123456126.com

                Author information
                © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 25 November 2019
                : 16 April 2020
                : 24 April 2020
                Page count
                Figures: 5, Tables: 4, Pages: 11, Words: 6507
                Funded by: National Key Sci‐Tech Special Project of China (No. 2018ZX10302204003)
                Funded by: Science Foundation of China
                Award ID: 81472282, 81802311
                Funded by: General Program from Shanghai Municipal Health Commission: NO201740249
                Funded by: Youth Program from Shanghai Municipal Health Commission
                Award ID: 20184Y0125
                Funded by: Shanghai Education Committee of Shuguang Plan
                Award ID: 18SG32
                Funded by: National Key Basic Research Program “973 project”
                Award ID: 2015CB555400
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:17.07.2020

                Oncology & Radiotherapy
                cell‐free dna,chromosomal instability,primary liver cancer
                Oncology & Radiotherapy
                cell‐free dna, chromosomal instability, primary liver cancer


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