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1
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Amaeshi LC, Okunade KS, Anorlu RI. Current landscape of cancer genomics research in sub-Saharan Africa - a review of literature. Front Oncol 2025; 15:1512005. [PMID: 40313245 PMCID: PMC12043467 DOI: 10.3389/fonc.2025.1512005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/26/2025] [Indexed: 05/03/2025] Open
Abstract
Cancer poses a significant public health challenge in sub-Saharan Africa, a region that has traditionally struggled with infectious diseases. Although communicable diseases remain the leading cause of mortality in sub-Saharan Africa (SSA), there has been a rise in the morbidity and mortality rates associated with non-communicable diseases (NCDs), in recent years. As of 2019, NCDs accounted for 37% of deaths, representing an increase from the 24% recorded in 2000. Cancer is fundamentally a genetic disorder, and genomic research has provided a deeper understanding of its biology leading to identification of biomarkers for early cancer detection and advancement in precision oncology. However, despite Africa's rich genomic diversity and significant cancer burden, the continent remains underrepresented in global genomic research. This underrepresentation is mainly due to challenges such as insufficient funding, inadequate infrastructure, and a limited pool of trained professionals. However, despite these obstacles, initiatives like the H3Africa Consortium, African BioGenome Project, and Prostate Cancer Transatlantic Consortium (CaPTC), amongst others, have made significant strides in funding and developing local capacity and infrastructure for genomic research. In this review, we discuss the unique genomic characteristics of common cancers in Africa, highlight challenges faced in the implementation of genomic research, and explore potential solutions and current initiatives instituted to foster genomic research in the region.
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Affiliation(s)
| | - Kehinde S. Okunade
- Oncology and Pathological Unit, Department of Obstetrics and Gynecology, College of Medicine, University of Lagos, Lagos, Nigeria
- Lagos University Teaching Hospital, Lagos, Nigeria
| | - Rose I. Anorlu
- Oncology and Pathological Unit, Department of Obstetrics and Gynecology, College of Medicine, University of Lagos, Lagos, Nigeria
- Lagos University Teaching Hospital, Lagos, Nigeria
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2
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Kibugu J, Munga L, Mburu D, Maloba F, Auma JE, Grace D, Lindahl JF. Dietary Mycotoxins: An Overview on Toxicokinetics, Toxicodynamics, Toxicity, Epidemiology, Detection, and Their Mitigation with Special Emphasis on Aflatoxicosis in Humans and Animals. Toxins (Basel) 2024; 16:483. [PMID: 39591238 PMCID: PMC11598113 DOI: 10.3390/toxins16110483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 11/28/2024] Open
Abstract
Mycotoxins are secondary metabolites of filamentous fungi and ubiquitous dietary contaminants. Aflatoxins, a group of mycotoxins with high prevalence and toxicity, have raised a high level of public health concern, the most prevalent and toxic being aflatoxin B1 (AFB1). Many aspects appertaining to AFB1 poisoning are not well understood. Yet this information is necessary to devise appropriate surveillance and mitigation strategies against human and animal aflatoxicosis. This review provides an in-depth update of work carried out on mycotoxin poisoning, particularly aflatoxicosis in humans and animals, to identify gaps in knowledge. Hypotheses explaining the functional significance of mycotoxins in fungal biology and their dietary epidemiological data are presented and briefly discussed. The toxicology of aflatoxins and the challenges of their mitigation are discussed in depth. It was concluded that the identification of potential mycotoxin-hazard-prone food items and quantification of the associated risk of cancer ailments in humans is a prime priority. There is a dearth of reliable sampling methodologies for estimating AFB1 in animal feed. Data update on AFB1 in animal feed and its implication in animal production, mitigation strategies, and elucidation of risk factors to this hazard is required. To reduce the burden of aflatoxins, surveillance employing predictive technology, and biocontrol strategies seem promising approaches.
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Affiliation(s)
- James Kibugu
- Biotechnology Research Institute, Kenya Agricultural and Livestock Research Organization, P.O. Box 362, Kikuyu 00902, Kenya;
- Department of Biochemistry, Microbiology and Biotechnology, School of Pure and Applied Sciences, Kenyatta University, P.O. Box 43844, Nairobi 00100, Kenya;
| | - Leonard Munga
- Department of Animal Science, School of Agriculture and Environmental Sciences, Kenyatta University, P.O. Box 43844, Nairobi 00100, Kenya;
| | - David Mburu
- Department of Biochemistry, Microbiology and Biotechnology, School of Pure and Applied Sciences, Kenyatta University, P.O. Box 43844, Nairobi 00100, Kenya;
| | - Fredrick Maloba
- Department of Zoological Sciences, School of Pure and Applied Sciences, Kenyatta University, P.O. Box 43844, Nairobi 00100, Kenya;
| | - Joanna E. Auma
- Biotechnology Research Institute, Kenya Agricultural and Livestock Research Organization, P.O. Box 362, Kikuyu 00902, Kenya;
| | - Delia Grace
- Department of Biosciences, International Livestock Research Institute, P.O. Box 30709, Nairobi 00100, Kenya;
- Natural Resources Institute, University of Greenwich, UK, Central Avenue, Chatham ME4 4TB, UK
| | - Johanna F. Lindahl
- Department of Animal Health and Antibiotic Strategies, Swedish Veterinary Agency, 75189 Uppsala, Sweden;
- Department of Medical Biochemistry and Microbiology, Uppsala University, 75123 Uppsala, Sweden
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3
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Basthi Mohan P, Lochan R, Shetty S. Biomarker in Hepatocellular Carcinoma. Indian J Surg Oncol 2024; 15:261-268. [PMID: 38817995 PMCID: PMC11133295 DOI: 10.1007/s13193-023-01858-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 11/29/2023] [Indexed: 06/01/2024] Open
Abstract
Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma (HCC) is contributed by various etiological factors like virus infection, excessive alcohol consumption, exposure to toxins, or metabolic disorders. Majority of patients are diagnosed with late-stage HCC, which restricts its management to only palliative care. HCC, if diagnosed early, increases the survival and quality of life. Currently available biomarker (alpha-fetoproteins) have several limitations, that impede the early diagnosis and staging of cancer. This warrants the continous search in pursuit of a novel biomarker. Several research works in diverse areas have contributed to the identification of various novel biomarkers that have shown multifaceted application in early disease diagnosis, which further aid in targeted and effective therapy that can prevent cancer progression. This improves the overall health status of the patient along with significant reduction in caretaker's burden. With the aid of novel technologies, several biomarkers have been investigated and validated in mutliple preliminary research works. Therefore in this review, we have outlined various novel biomarkers that showed promising outcomes in their trials and we have highlighted the developing areas that act as game changers in cancer diagnosis and management.
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Affiliation(s)
- Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Rajiv Lochan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
- Lead Consultant Surgeon - HPB and Liver transplantation Surgery, Manipal Hospital, Bengaluru, 560017 Karnataka India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
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4
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Kumar S, Nadda N, Quadri A, Kumar R, Paul S, Tanwar P, Gamanagatti S, Dash NR, Saraya A, Shalimar, Nayak B. Assessments of TP53 and CTNNB1 gene hotspot mutations in circulating tumour DNA of hepatitis B virus-induced hepatocellular carcinoma. Front Genet 2023; 14:1235260. [PMID: 37593116 PMCID: PMC10429180 DOI: 10.3389/fgene.2023.1235260] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
Background: Hepatitis B virus (HBV) infection is one of the major causes of chronic liver disease, which progresses from chronic hepatitis B (CHB) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Early detection and laboratory-based screening of hepatocellular carcinoma are still major challenges. This study was undertaken to determine whether the cancer hallmark gene signatures that are released into circulation as circulating tumour DNA (ctDNA) can be used as a liquid biopsy marker for screening, early detection, and prognosis of HCC. Methods: A total of 130 subjects, including HBV-HCC (n = 80), HBV-cirrhotic and non-cirrhotic (n = 35), and healthy (n = 15) controls, were evaluated for TP53 and beta-catenin (CTNNB1) gene hotspot mutations in ctDNA by Sanger-based cycle sequencing and droplet digital PCR (ddPCR) assays. Mutation detection frequency, percentage mutant fractions, and their association with tumour stage, mortality, and smoking habits were determined. Results: Sanger-based cycle sequencing was carried out for 32 HCC patients. Predict SNP Tools analysis indicated several pathogenic driver mutations in the ctDNA sequence, which include p.D228N, p.C229R, p.H233R, p.Y234D, p.S240T, p.G245S, and p.R249M for TP53 gene exon 7 and p.S33T for CTNNB1 gene exon 3. The TP53 c.746G>T (p.R249M) mutation was detected predominately (25% cases) by sequencing, but there was no dominant mutation at position c.747G>T (p.R249S) that was reported for HBV-HCC patients. A dual-probe ddPCR assay was developed to determine mutant and wild-type copy numbers of TP53 (p.R249M and p.R249S) and CTNNB1 (p.S45P) and their percentage mutant fraction in all 130 subjects. The TP53 R249M and CTNNB1 S45P mutations were detected in 31.25% and 26.25% of HCC patients, respectively, with a high mutant-to-wild-type fraction percentage (1.81% and 1.73%), which is significant as compared to cirrhotic and non-cirrhotic patients. Poor survival was observed in HCC patients with combined TP53 and CTNNB1 gene driver mutations. The TP53 R249M mutation was also significantly (p < 0.0001) associated with smoking habits (OR, 11.77; 95% CI, 3.219-36.20), but not the same for the TP53 R249S mutation. Conclusion: Screening of ctDNA TP53 and CTNNB1 gene mutations by ddPCR may be helpful for early detection and identifying the risk of HCC progression.
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Affiliation(s)
- Sonu Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Neeti Nadda
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Afnan Quadri
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Rahul Kumar
- Laboratory Oncology Unit (BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | - Shashi Paul
- Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Pranay Tanwar
- Laboratory Oncology Unit (BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | | | - Nihar Ranjan Dash
- Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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5
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Zhu G, Liu W, Tang Z, Qu W, Fang Y, Jiang X, Song S, Wang H, Tao C, Zhou P, Huang R, Gao J, Sun H, Ding Z, Peng Y, Dai Z, Zhou J, Fan J, Shi Y. Serial circulating tumor DNA to predict early recurrence in patients with hepatocellular carcinoma: a prospective study. Mol Oncol 2022; 16:549-561. [PMID: 34543520 PMCID: PMC8763657 DOI: 10.1002/1878-0261.13105] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/25/2021] [Accepted: 09/17/2021] [Indexed: 12/12/2022] Open
Abstract
We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma-free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next-generation sequencing before and after operation. Whole-exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre- and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow-up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time-points was associated with significantly shorter recurrence-free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real-time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC.
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6
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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7
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Tan P, Grundy L, Makary P, Eng KH, Ramsay G, Bekheit M. The value of liquid biopsy in the diagnosis and staging of hepatocellular carcinoma: a systematic review. Transl Gastroenterol Hepatol 2021; 6:54. [PMID: 34805576 PMCID: PMC8573369 DOI: 10.21037/tgh.2020.01.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Blood-borne tumour markers in the form of circulating tumour cells (CTCs) are of intense research interest in the diagnostic and prognostic work-up of hepatocellular carcinoma (HCC). METHODS This is a meta-analysis. Using a PICO strategy, adults with HCC was the population, with the individual CTCs as the intervention and comparators. The primary outcome was the sensitivity and specificity of HCC detection with tumour specific single gene methylation alteration. Secondary outcomes were the comparison using specific assay methods and the effect of early vs. late stages on CTC positivity. We included patients with HCC who had samples taken from peripheral blood and had sufficient data to assess the outcome data. ASSIA, Cochrane library, EMbase, Medline, PubMed and the knowledge network Scotland were systematically searched with appropriate Mesh terms employed. The quality assessment of diagnostic accuracy studies (QUADAS) was used to ensure quality of data. Statistical analysis was performed using the 'Rev Man' meta-analysis soft ward for Windows. RESULTS The review included 36 studies, with a total of 5,853 patients. Here, we found that AFP has the highest overall diagnostic performance. The average Youden index amongst all CTC was 0.46 with a mode and median of 0.5 with highest of 0.87 and lowest of 0.01. CONCLUSIONS The available literature provides weak evidence that there is potential in the use of CTC, however the lack of a standardised procedure in the study of CTC contribute to the lack of consensus of use. Future research should include large scaled, standardized studies for the diagnostic accuracy of CTCs.
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Affiliation(s)
- Poh Tan
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Lisa Grundy
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Peter Makary
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | | | - George Ramsay
- Rowette institute of Health Sciences, Medical School, University of Aberdeen, Aberdeen, UK
| | - Mohamed Bekheit
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
- Department of Surgery, El Kabbary Hospital, Alexandria, Egypt
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8
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Jiao J, Sanchez JI, Thompson EJ, Mao X, McCormick JB, Fisher-Hoch SP, Futreal PA, Zhang J, Beretta L. Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics. Int J Mol Sci 2021; 22:ijms22147411. [PMID: 34299031 PMCID: PMC8304329 DOI: 10.3390/ijms22147411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/03/2023] Open
Abstract
Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
| | - Jessica I. Sanchez
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
| | - Erika J. Thompson
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Xizeng Mao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Joseph B. McCormick
- Brownsville Regional Campus, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX 78520, USA; (J.B.M.); (S.P.F.-H.)
| | - Susan P. Fisher-Hoch
- Brownsville Regional Campus, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX 78520, USA; (J.B.M.); (S.P.F.-H.)
| | - P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (X.M.); (P.A.F.); (J.Z.)
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (J.J.); (J.I.S.)
- Correspondence: ; Tel.: +1-713-792-9100
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9
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Rotimi SO, Rotimi OA, Salhia B. A Review of Cancer Genetics and Genomics Studies in Africa. Front Oncol 2021; 10:606400. [PMID: 33659210 PMCID: PMC7917259 DOI: 10.3389/fonc.2020.606400] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is the second leading cause of death globally and is projected to overtake infectious disease as the leading cause of mortality in Africa within the next two decades. Cancer is a group of genomic diseases that presents with intra- and inter-population unique phenotypes, with Black populations having the burden of morbidity and mortality for most types. At large, the prevention and treatment of cancers have been propelled by the understanding of the genetic make-up of the disease of mostly non-African populations. By the same token, there is a wide knowledge gap in understanding the underlying genetic causes of, and genomic alterations associated with, cancer among black Africans. Accordingly, we performed a review of the literature to survey existing studies on cancer genetics/genomics and curated findings pertaining to publications across multiple cancer types conducted on African populations. We used PubMed MeSH terms to retrieve the relevant publications from 1990 to December 2019. The metadata of these publications were extracted using R text mining packages: RISmed and Pubmed.mineR. The data showed that only 0.329% of cancer publications globally were on Africa, and only 0.016% were on cancer genetics/genomics from Africa. Although the most prevalent cancers in Africa are cancers of the breast, cervix, uterus, and prostate, publications representing breast, colorectal, liver, and blood cancers were the most frequent in our review. The most frequently reported cancer genes were BRCA1, BRCA2, and TP53. Next, the genes reported in the reviewed publications’ abstracts were extracted and annotated into three gene ontology classes. Genes in the cellular component class were mostly associated with cell part and organelle part, while those in biological process and molecular function classes were mainly associated with cell process, biological regulation, and binding, and catalytic activity, respectively. Overall, this review highlights the paucity of research on cancer genomics on African populations, identified gaps, and discussed the need for concerted efforts to encourage more research on cancer genomics in Africa.
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Affiliation(s)
- Solomon O Rotimi
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Biochemistry, Covenant University, Ota, Nigeria
| | - Oluwakemi A Rotimi
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Biochemistry, Covenant University, Ota, Nigeria
| | - Bodour Salhia
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA, United States
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10
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von Felden J, Garcia-Lezana T, Schulze K, Losic B, Villanueva A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 2020; 69:2025-2034. [PMID: 32883873 DOI: 10.1136/gutjnl-2019-320282] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/21/2020] [Accepted: 07/27/2020] [Indexed: 02/06/2023]
Abstract
With increasing knowledge on molecular tumour information, precision oncology has revolutionised the medical field over the past years. Liquid biopsy entails the analysis of circulating tumour components, such as circulating tumour DNA, tumour cells or tumour-derived extracellular vesicles, and has thus come as a handy tool for personalised medicine in many cancer entities. Clinical applications under investigation include early cancer detection, prediction of treatment response and molecular monitoring of the disease, for example, to comprehend resistance patterns and clonal tumour evolution. In fact, several tests for blood-based mutation profiling are already commercially available and have entered the clinical field.In the context of hepatocellular carcinoma, where access to tissue specimens remains mostly limited to patients with early stage tumours, liquid biopsy approaches might be particularly helpful. A variety of translational liquid biopsy studies have been carried out to address clinical needs, such as early hepatocellular carcinoma detection and prediction of treatment response. To this regard, methylation profiling of circulating tumour DNA has evolved as a promising surveillance tool for early hepatocellular carcinoma detection in populations at risk, which might soon transform the way surveillance programmes are implemented. This review summarises recent developments in the liquid biopsy oncological space and, in more detail, the potential implications in the clinical management of hepatocellular carcinoma. It further outlines technical peculiarities across liquid biopsy technologies, which might be helpful for interpretation by non-experts.
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Affiliation(s)
- Johann von Felden
- Department of Internal Medicine, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Teresa Garcia-Lezana
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA
| | - Kornelius Schulze
- Department of Internal Medicine, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Bojan Losic
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Augusto Villanueva
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA .,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States
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11
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Chen L, Chen Y, Feng YL, Zhu Y, Wang LQ, Hu S, Cheng P. Tumor circulome in the liquid biopsies for digestive tract cancer diagnosis and prognosis. World J Clin Cases 2020; 8:2066-2080. [PMID: 32548136 PMCID: PMC7281040 DOI: 10.12998/wjcc.v8.i11.2066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 02/05/2023] Open
Abstract
Digestive tract cancer is one of the main diseases that endanger human health. At present, the early diagnosis of digestive tract tumors mainly depends on serology, imaging, endoscopy, and so on. Although tissue specimens are the gold standard for cancer diagnosis, with the rapid development of precision medicine in cancer, the demand for dynamic monitoring of tumor molecular characteristics has increased. Liquid biopsy involves the collection of body fluids via non-invasive approaches, and analyzes biological markers such as circulating tumor cells, circulating tumor DNA, circulating cell-free DNA, microRNAs, and exosomes. In recent years, liquid biopsy has become more and more important in the diagnosis and prognosis of cancer in clinical practice due to its convenience, non-invasiveness, high specificity and it overcomes temporal-spatial heterogeneity. Therefore, this review summarizes the current evidence on liquid biopsies in digestive tract cancers in relation to diagnosis and prognosis.
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Affiliation(s)
- Long Chen
- Department of Radiotherapy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yu Chen
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yuan-Ling Feng
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Yan Zhu
- Department of Respiratory, Shulan Hospital, Hangzhou 310004, Zhejiang Province, China
| | - Li-Quan Wang
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Shen Hu
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Pu Cheng
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310052, Zhejiang Province, China
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12
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Hartwig A, Arand M, Epe B, Guth S, Jahnke G, Lampen A, Martus HJ, Monien B, Rietjens IMCM, Schmitz-Spanke S, Schriever-Schwemmer G, Steinberg P, Eisenbrand G. Mode of action-based risk assessment of genotoxic carcinogens. Arch Toxicol 2020; 94:1787-1877. [PMID: 32542409 PMCID: PMC7303094 DOI: 10.1007/s00204-020-02733-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 12/16/2022]
Abstract
The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as "omics" approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.
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Affiliation(s)
- Andrea Hartwig
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, 8057, Zurich, Switzerland
| | - Bernd Epe
- Institute of Pharmacy and Biochemistry, University of Mainz, 55099, Mainz, Germany
| | - Sabine Guth
- Department of Toxicology, IfADo-Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Gunnar Jahnke
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany
| | - Alfonso Lampen
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany
| | - Hans-Jörg Martus
- Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland
| | - Bernhard Monien
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Simone Schmitz-Spanke
- Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Henkestr. 9-11, 91054, Erlangen, Germany
| | - Gerlinde Schriever-Schwemmer
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany
| | - Pablo Steinberg
- Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany
| | - Gerhard Eisenbrand
- Retired Senior Professor for Food Chemistry and Toxicology, Kühler Grund 48/1, 69126, Heidelberg, Germany.
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13
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Lolomadze EA, Kometova VV, Rodionov VV. Circulating RNA in blood plasma as diagnostic tool for clinical oncology. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2020. [DOI: 10.24075/brsmu.2020.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
One of the key challenges facing today’s oncology is the discovery of early predictors of malignant neoplasms in patients’ biological samples. Liquid biopsy is a noninvasive diagnostic technique based on the detection and isolation of tumor cells, tumor-derived nucleic acid and exosomes circulating in the blood plasma of cancer patients. There is a plethora of research studies of circulating tumor DNA in patients with MN. The active proliferation of tumor cells occurs in the backdrop of altered gene expression. The presence of tissue-specific transcripts in the circulating RNA fraction suggests that levels of circulating RNA reflect the development of the primary tumor. We think that cell-free RNA circulating in the blood plasma is a promising molecular biomarker for early cancer detection.
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Affiliation(s)
- EA Lolomadze
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - VV Kometova
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - VV Rodionov
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
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14
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Alvarez CS, Ortiz J, Bendfeldt‐Avila G, Xie Y, Wang M, Wu D, Higson H, Lee E, Teshome K, Barnoya J, Kleiner DE, Groopman JD, Orozco R, McGlynn KA, Gharzouzi E, Dean M. Analysis of TP53 aflatoxin signature mutation in hepatocellular carcinomas from Guatemala: A cross-sectional study (2016-2017). Health Sci Rep 2020; 3:e155. [PMID: 32382660 PMCID: PMC7202218 DOI: 10.1002/hsr2.155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/18/2020] [Accepted: 03/24/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND AIMS Guatemala has the highest incidence of hepatocellular carcinoma (HCC) in the Western hemisphere. The major risk factors in Guatemala are not well characterized, but the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) appears to be low, while the prevalence of aflatoxin (AFB1) exposure appears to be high. To examine whether AFB1 may contribute to the elevated incidence of HCC in Guatemala, this study examined the frequency of the AFB1-signature mutation in the TP53 gene (R249S) as well as other somatic mutations. In addition, we assessed whether the frequency of the TP53 mutation differed by sex. METHODS Formalin-fixed, paraffin-embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City between 2016 and 2017. In addition, tumor tissues preserved in RNAlater were also obtained. Sociodemographic and clinical information including HBV and HCV status were collected. Targeted sequencing of TP53 was performed in the FFPE samples, and a panel of 253 cancer-related genes was sequenced in the RNAlater samples. RESULTS Ninety-one FFPE tissues were examined, from 52 men and 39 women. Median (IQR) age at diagnosis was 62 (51-70). Among those with known HBV and HCV status, two were HBV+ and three were HCV+. Overall, 47% of the HCCs had a TP53 mutation. The AFB1-signature R249S mutation was present in 24%. No overlap between the R249S mutation and HBV+ was observed in this cohort. Among 18 RNAlater samples examined, 44% had any TP53 mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes. CONCLUSIONS The presence of the TP53 R249S mutation in the samples studied suggests that AFB1 may contribute to the high incidence of HCC in Guatemala. The proportion of HBV+ tumors was low, suggesting that AFB1 may be associated with HCC in the absence of concomitant HBV infection. Further investigation of AFB1 and other risk factors for HCC in Guatemala is warranted.
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Affiliation(s)
- Christian S. Alvarez
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMaryland
| | - Jeremy Ortiz
- Instituto de Cancerología/INCANGuatemala CityGuatemala
| | | | - Yi Xie
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMaryland
| | - Mingyi Wang
- Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research IncFrederick National Laboratory for Cancer ResearchGaithersburgMaryland
| | - Dongjing Wu
- Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research IncFrederick National Laboratory for Cancer ResearchGaithersburgMaryland
| | - Herbert Higson
- Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research IncFrederick National Laboratory for Cancer ResearchGaithersburgMaryland
| | - Elisa Lee
- Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research IncFrederick National Laboratory for Cancer ResearchGaithersburgMaryland
| | - Kedest Teshome
- Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research IncFrederick National Laboratory for Cancer ResearchGaithersburgMaryland
| | | | - David E. Kleiner
- Laboratory of PathologyCenter for Cancer Research, NCI, NIHBethesdaMaryland
| | - John D. Groopman
- Department of Environmental Health and Engineering, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMaryland
- Department of Epidemiology, Bloomberg School of Public HealthJohns Hopkins, UniversityBaltimoreMaryland
| | - Roberto Orozco
- Department of PathologyHospital General San Juan de DiosGuatemala CityGuatemala
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMaryland
| | | | - Michael Dean
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMaryland
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15
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Luo Z, Zhang M, Cui R, Tili E, Kim T, Lee TJ, Peng Y, Croce C. A negative feedback regulatory loop between miR-138 and TP53 is mediated by USP10. Oncotarget 2019; 10:6288-6296. [PMID: 31695837 PMCID: PMC6824876 DOI: 10.18632/oncotarget.27275] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/10/2019] [Indexed: 02/05/2023] Open
Abstract
TP53 is a critical tumor suppressor. In approximately 50% of human cancers the TP53 gene is either lost or mutated. The expression level of TP53 in the cells is tightly controlled by a fine-tune machinery, mainly through the Mdm2-mediated ubiquitination pathway. On the other side, the ubiquitinated TP53 could be reversed and stabilized by USP7 and USP10, to keep the amount of TP53 in check. MicroRNAs can negatively regulate TP53 expression levels through direct targeting or positively regulate TP53 function through the repression of negative regulators of TP53. Here we report that microRNA-138 controls TP53 expression by directly targeting USP10. Furthermore, TP53 represses microRNA-138 expression, forming a negative feedback regulatory loop. This finding adds another layer of complexity to the TP53 network.
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Affiliation(s)
- Zhenghua Luo
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Manchao Zhang
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Ri Cui
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Esmerina Tili
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Taewan Kim
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Tae Jin Lee
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Yong Peng
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Carlo Croce
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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16
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Rice A, Del Rio Hernandez A. The Mutational Landscape of Pancreatic and Liver Cancers, as Represented by Circulating Tumor DNA. Front Oncol 2019; 9:952. [PMID: 31608239 PMCID: PMC6769086 DOI: 10.3389/fonc.2019.00952] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 09/09/2019] [Indexed: 02/06/2023] Open
Abstract
The mutational landscapes of pancreatic and liver cancers share many common genetic alterations which drive cancer progression. However, these mutations do not occur in all cases of these diseases, and this tumoral heterogeneity impedes diagnosis, prognosis, and therapeutic development. One minimally invasive method for the evaluation of tumor mutations is the analysis of circulating tumor DNA (ctDNA), released through apoptosis, necrosis, and active secretion by tumor cells into various body fluids. By observing mutations in those genes which promote transformation by controlling the cell cycle and oncogenic signaling pathways, a representation of the mutational profile of the tumor is revealed. The analysis of ctDNA is a promising technique for investigating these two gastrointestinal cancers, as many studies have reported on the accuracy of ctDNA assessment for diagnosis and prognosis using a variety of techniques.
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Affiliation(s)
- Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London, United Kingdom
| | - Armando Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London, United Kingdom
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17
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Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol 2019; 25:4199-4212. [PMID: 31435173 PMCID: PMC6700689 DOI: 10.3748/wjg.v25.i30.4199] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/28/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
The huge prognostic difference between early and late stage hepatocellular carcinoma (HCC) is a challenging diagnostic problem. Alpha-fetoprotein is the mostly widely used biomarker for HCC used in the clinic, however it’s sensitivity and specificity of is not optimal. The development and application of multiple biotechnologies, including next generation sequencing, multiple “omics” data, that include genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics has been used for HCC diagnostic biomarker screening. Effective biomarkers/panels/models have been identified and validated at different clinical levels. A large proportion of these have a good diagnostic performance for HCC, especially for early HCC. In this article, we reviewed the various HCC biomarkers derived from “omics” data and discussed the advantages and disadvantages for diagnosis HCC.
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Affiliation(s)
- Xiao-Na Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Dan-Ni Cui
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yu-Fang Li
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yun-He Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Gang Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lei Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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18
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Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol 2019. [DOI: 10.3748/wjg.v25.i29.4199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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19
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Jain S, Lin SY, Song W, Su YH. Urine-Based Liquid Biopsy for Nonurological Cancers. Genet Test Mol Biomarkers 2019; 23:277-283. [PMID: 30986103 DOI: 10.1089/gtmb.2018.0189] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIMS The use of circulating cell-free DNA for detection of cancer genetics has been studied extensively. Liquid biopsy often refers to the use of blood as a minimally invasive source of body fluid for detecting circulating tumor DNA (ctDNA). However, urine collection, which is completely noninvasive, has been shown to also have great promise to serve as an alternate body fluid source for ctDNA. In this review article, we focus on the clinical utility of urine for genetic liquid biopsy of nonurological cancers. CONCLUSION Although still in early stages as compared with blood-based liquid biopsy, recent studies have demonstrated the value of urine-based liquid biopsies for: nonurological cancer screening; early detection; monitoring for recurrence and metastasis; and therapeutic efficacy. Overall, the completely noninvasive and patient-friendly nature of the urine-based biopsy warrants further development and offers a promising alternative to blood-based biopsies.
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Affiliation(s)
- Surbhi Jain
- 1 JBS Science, Inc., Doylestown, Pennsylvania
| | | | - Wei Song
- 1 JBS Science, Inc., Doylestown, Pennsylvania
| | - Ying-Hsiu Su
- 2 Department of Translational Medical Science, The Baruch S. Blumberg Institute, Doylestown, Pennsylvania
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20
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Howell J, Atkinson SR, Pinato DJ, Knapp S, Ward C, Minisini R, Burlone ME, Leutner M, Pirisi M, Büttner R, Khan SA, Thursz M, Odenthal M, Sharma R. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma. Eur J Cancer 2019; 116:56-66. [PMID: 31173963 DOI: 10.1016/j.ejca.2019.04.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/03/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
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.
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Affiliation(s)
- Jessica Howell
- 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
| | - Stephen R Atkinson
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Susanne Knapp
- 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
| | - Caroline Ward
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Rosalba Minisini
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Michela E Burlone
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Monica Leutner
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Reinhard Büttner
- 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
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Mark Thursz
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Margarete Odenthal
- 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
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK.
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21
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Wang H, Liao P, Zeng SX, Lu H. It takes a team: a gain-of-function story of p53-R249S. J Mol Cell Biol 2019; 11:277-283. [PMID: 30608603 PMCID: PMC6487778 DOI: 10.1093/jmcb/mjy086] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 11/03/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022] Open
Abstract
Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.
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Affiliation(s)
- Huai Wang
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
- School of Public Health, Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
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22
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Rushing BR, Selim MI. Aflatoxin B1: A review on metabolism, toxicity, occurrence in food, occupational exposure, and detoxification methods. Food Chem Toxicol 2019; 124:81-100. [DOI: 10.1016/j.fct.2018.11.047] [Citation(s) in RCA: 325] [Impact Index Per Article: 54.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 12/30/2022]
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23
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Su YH, Kim AK, Jain S. Liquid biopsies for hepatocellular carcinoma. Transl Res 2018; 201:84-97. [PMID: 30056068 PMCID: PMC6483086 DOI: 10.1016/j.trsl.2018.07.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/18/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the world's second leading cause of cancer death; 82.4% of patients die within 5 years. This grim prognosis is the consequence of a lack of effective early detection tools, limited treatment options, and the high frequency of HCC recurrence. Advances in the field of liquid biopsy hold great promise in improving early detection of HCC, advancing patient prognosis, and ultimately increasing the survival rate. In an effort to address the current challenges of HCC screening and management, several studies have identified and evaluated liver-cancer-associated molecular signatures such as genetic alterations, methylation, and noncoding RNA expression in the form of circulating biomarkers in body fluids and circulating tumor cells of HCC patients. In this review, we summarize the recent progress in HCC liquid biopsy, organized by the intended clinical application of the reported study.
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Affiliation(s)
- Ying-Hsiu Su
- The Baruch S. Blumberg Institute, Doylestown, Pennsylvania.
| | - Amy K Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore Maryland.
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, Pennsylvania.
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24
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Marchio A, Amougou Atsama M, Béré A, Komas NP, Noah Noah D, Atangana PJA, Camengo-Police SM, Njouom R, Bekondi C, Pineau P. Droplet digital PCR detects high rate of TP53 R249S mutants in cell-free DNA of middle African patients with hepatocellular carcinoma. Clin Exp Med 2018; 18:421-431. [PMID: 29749584 DOI: 10.1007/s10238-018-0502-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/04/2018] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is still a major killing malignancy in sub-Saharan Africa. Lifelong intoxication with aflatoxin B1 is considered as one of the primary causes of this situation. The role of aflatoxin in HCC from a given population is commonly estimated through the prevalence of R249S mutation of TP53, a hallmark for previous exposure to the mycotoxin. However, the role of AFB1 is barely known in large part of Africa. We conducted a survey on circulating cell-free DNA from 149 patients with HCC and 213 control subjects with and without liver diseases from Cameroon and Central African Republic using droplet digital PCR technique. We observed a mutation prevalence of 24.8% (n = 37/149) in patients with tumor and 5.6% (n = 12/213) in controls (P = 2.2E-07). Patients with mutations usually displayed significantly increased circulating alpha-fetoprotein (AFP) values, high hepatitis B virus (HBV) DNA loads as well as worsened values of blood cells count. Interestingly, the fraction of droplets positive for R249S was significantly larger in patients with liver cancer (15.3 ± 3.7%) than in controls (0.5 ± 0.3%, P = 7.1E-04). Our survey indicates that AFB1 is instrumental for HCC development in Middle Africa and that droplet digital PCR might be used in the region both to diagnose HCC and to conduct public health surveys on populations at risk of chronic aflatoxin intoxication.
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Affiliation(s)
- Agnès Marchio
- Unité "Organisation Nucléaire et Oncogenèse," INSERM U993, Institut Pasteur, 28, rue du Docteur Roux, 752724, Paris Cedex 15, France
| | | | - Aubin Béré
- Unité de Rétrovirologie et Virus Oncogènes, Institut Pasteur de Bangui, Bangui, Central African Republic
| | - Narcisse-Patrice Komas
- Laboratoire des Hépatites Virales, Institut Pasteur de Bangui, Bangui, Central African Republic
| | | | | | | | - Richard Njouom
- Service de Virologie, Centre Pasteur du Cameroun, Yaoundé, Cameroun
| | - Claudine Bekondi
- Unité de Rétrovirologie et Virus Oncogènes, Institut Pasteur de Bangui, Bangui, Central African Republic
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse," INSERM U993, Institut Pasteur, 28, rue du Docteur Roux, 752724, Paris Cedex 15, France.
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25
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Ng CKY, Di Costanzo GG, Terracciano LM, Piscuoglio S. Circulating Cell-Free DNA in Hepatocellular Carcinoma: Current Insights and Outlook. Front Med (Lausanne) 2018; 5:78. [PMID: 29632864 PMCID: PMC5880118 DOI: 10.3389/fmed.2018.00078] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 03/08/2018] [Indexed: 12/25/2022] Open
Abstract
Over the past decade, the advancements in massively parallel sequencing have provided a new paradigm in biomedical research to uncover the genetic basis of human diseases. Integration of ‘omics information has begun transforming clinical management of cancer patients in terms of diagnostics and treatment options, giving rise to the era of precision medicine. Currently, nucleic acids for molecular profiling for patients diagnosed with hepatocellular carcinoma (HCC) are typically obtained from resected tumor materials or transplanted neoplastic liver and occasionally from biopsies. Given the intrinsic risks associated with such invasive procedures, circulating cell-free DNA (cfDNA) has been proposed as an alternative source for tumor DNA. Circulating cfDNA is a type of cell-free nucleic acid that derives from apoptotic, necrotic, as well as living eukaryotic cells. Importantly, the detection of abnormal forms of circulating cfDNA that originate from cancer cells provides a new tool for cancer detection, disease monitoring, and molecular profiling. Currently, cfDNA is beginning to be adopted into clinical practice as a non-invasive tool to monitor disease by tracking the evolution of disease-specific genetic alterations in several major cancer types. Moreover, cfDNA is demonstrating potential clinical value as a surrogate to assess the molecular makeup of tumors and to overcome the sampling biases inherent to intra-tumor genetic heterogeneity, especially in the metastatic setting. With the improvements in ‘omics and molecular biology techniques, coupled with the increasing understanding in the molecular pathogenesis of cancer, it can be anticipated that the detection and analysis of cfDNA will become more specific and sensitive and thus enable cfDNA analysis to be used as a diagnostic aid in patients with early-stage disease and perhaps even in a screening setting. In this review, we provide an overview of the latest findings on the role and potential utility of cfDNA analysis in the diagnosis, management, and screening of HCC.
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Affiliation(s)
- Charlotte K Y Ng
- Institute of Pathology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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26
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Jiao J, Niu W, Wang Y, Baggerly K, Ye Y, Wu X, Davenport D, Almeda JL, Betancourt-Garcia MM, Forse RA, Stevenson HL, Watt GP, McCormick JB, Fisher-Hoch SP, Beretta L. Prevalence of Aflatoxin-Associated TP53R249S Mutation in Hepatocellular Carcinoma in Hispanics in South Texas. Cancer Prev Res (Phila) 2018. [DOI: 10.1158/1940-6207.capr-17-0235-at] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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27
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Jiao J, Niu W, Wang Y, Baggerly K, Ye Y, Wu X, Davenport D, Almeda JL, Betancourt-Garcia MM, Forse RA, Stevenson HL, Watt GP, McCormick JB, Fisher-Hoch SP, Beretta L. Prevalence of Aflatoxin-Associated TP53R249S Mutation in Hepatocellular Carcinoma in Hispanics in South Texas. Cancer Prev Res (Phila) 2017; 11:103-112. [PMID: 29089331 DOI: 10.1158/1940-6207.capr-17-0235] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/21/2017] [Accepted: 10/26/2017] [Indexed: 02/07/2023]
Abstract
We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas. We measured TP53R249S somatic mutation, hallmark of aflatoxin etiology in HCC, using droplet digital PCR and RFLP. TP53R249S mutation was detected in 3 of 41 HCC tumors from Hispanics in South Texas (7.3%). We also measured TP53R249S mutation in plasma cell-free DNA (cfDNA) from 218 HCC patients and 96 Hispanic subjects with advanced fibrosis or cirrhosis, from South Texas. The mutation was detected only in Hispanic and Asian HCC patients, and patients harboring TP53R249S mutation were significantly younger and had a shorter overall survival. The mutation was not detected in any Hispanic subject with advanced fibrosis or cirrhosis. Genes involved in cell-cycle control of chromosomal replication and in BRCA1-dependent DNA damage response were enriched in HCCs with TP53R249S mutation. The E2F1 family members, E2F1 and E2F4, were identified as upstream regulators. TP53R249S mutation was detected in 5.7% to 7.3% of Hispanics with HCC in South Texas. This mutation was associated with a younger age and worse prognosis. TP53R249S was however not detected in Hispanics in South Texas with cirrhosis or advanced fibrosis. Aflatoxin exposure may contribute to a small number of HCCs in Hispanics in South Texas, but the detection of TP53R249S mutation in plasma cfDNA is not a promising biomarker of risk assessment for HCC in subjects with cirrhosis or advanced fibrosis in this population. Cancer Prev Res; 11(2); 103-12. ©2017 AACR.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Weibo Niu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ying Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Keith Baggerly
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yuanqing Ye
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dewitt Davenport
- Doctor's Hospital at Renaissance, Edinburg, Texas.,University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas
| | - Jose Luis Almeda
- Doctor's Hospital at Renaissance, Edinburg, Texas.,University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas
| | | | - R Armour Forse
- Doctor's Hospital at Renaissance, Edinburg, Texas.,University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas
| | - Gordon P Watt
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas
| | - Joseph B McCormick
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas
| | - Susan P Fisher-Hoch
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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28
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Howell JA, Khan SA, Knapp S, Thursz MR, Sharma R. The clinical role of circulating free tumor DNA in gastrointestinal malignancy. Transl Res 2017; 183:137-154. [PMID: 28056336 DOI: 10.1016/j.trsl.2016.12.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 10/14/2016] [Accepted: 12/06/2016] [Indexed: 02/06/2023]
Abstract
Circulating cell-free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor-derived circulating cell-free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated "liquid biopsy" of cancer, facilitating real-time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies.
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Affiliation(s)
- Jessica A Howell
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK; Centre for Population Health, MacFarlane-Burnet Institute, Melbourne, Australia; Department of Medicine, The University of Melbourne, Melbourne, Australia.
| | - Shahid A Khan
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Susanne Knapp
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Mark R Thursz
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Rohini Sharma
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College, London, UK
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29
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Lou J, Zhang L, Lv S, Zhang C, Jiang S. Biomarkers for Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2017; 9:1-9. [PMID: 28469485 PMCID: PMC5345949 DOI: 10.1177/1179299x16684640] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/26/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The HCC diagnosis is usually achieved by biomarkers, which can also help in prognosis prediction. Furthermore, it might represent certain therapeutic interventions through some combinations of biomarkers. Here, we review on our current understanding of HCC biomarkers.
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Affiliation(s)
- Jiatao Lou
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - LingFei Zhang
- Center for RNA Research, State Key Laboratory of Molecular Biology, Chinese Academy of Sciences (CAS), Shanghai, China.,Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaogang Lv
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chenzi Zhang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuai Jiang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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30
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Ledda C, Loreto C, Zammit C, Marconi A, Fago L, Matera S, Costanzo V, Sanzà GF, Palmucci S, Ferrante M, Costa C, Fenga C, Biondi A, Pomara C, Rapisarda V. Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review). Mol Med Rep 2017; 15:511-533. [PMID: 28000892 PMCID: PMC5364850 DOI: 10.3892/mmr.2016.6046] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/01/2016] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the second leading worldwide cause of cancer‑associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well‑established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non‑infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non‑specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non‑infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Caterina Ledda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Carla Loreto
- Human Anatomy and Histology, Department of Biomedical and Biotechnology Sciences, University of Catania, I-95123 Catania, Italy
| | - Christian Zammit
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
| | - Andrea Marconi
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Lucrezia Fago
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Serena Matera
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Valentina Costanzo
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Giovanni Fuccio Sanzà
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Stefano Palmucci
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Margherita Ferrante
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Chiara Costa
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Concettina Fenga
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Antonio Biondi
- General Surgery, Department of General Surgery and Medical-Surgical Specialties, University of Catania, I-95123 Catania, Italy
| | - Cristoforo Pomara
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
- Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, I-71122 Foggia, Italy
| | - Venerando Rapisarda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
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31
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Tang JC, Feng YL, Guo T, Xie AY, Cai XJ. Circulating tumor DNA in hepatocellular carcinoma: trends and challenges. Cell Biosci 2016; 6:32. [PMID: 27182434 PMCID: PMC4866298 DOI: 10.1186/s13578-016-0100-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/02/2016] [Indexed: 12/18/2022] Open
Abstract
Molecular characterization of individual patients’ tumor cells is becoming increasingly important in offering effective treatment for patients in clinical practice. Recent advances in the field have indicated that circulating tumor DNA (ctDNA) has huge potential to serve as a biomarker for early detection and precision treatment as well as prognosis of hepatocellular carcinoma (HCC). As ctDNA in HCC patients harbors the molecular characteristics of HCC tumor cells, ctDNA analysis in the blood may be sufficient for convenient, non-invasive and accurate detection, providing information for HCC diagnosis, treatment and prognosis. In this review, we will summarize and discuss current trends and challenges of ctDNA application in HCC.
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Affiliation(s)
- Jia-Cheng Tang
- Zhejiang Province Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China
| | - Yi-Li Feng
- Zhejiang Province Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China ; Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Tao Guo
- Zhejiang Province Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China ; Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - An-Yong Xie
- Zhejiang Province Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China ; Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiu-Jun Cai
- Zhejiang Province Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China
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32
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Howell JA, Sharma R. The clinical role of 'liquid biopsy' in hepatocellular carcinoma. Hepat Oncol 2015; 3:45-55. [PMID: 30191026 DOI: 10.2217/hep.15.38] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 09/28/2015] [Indexed: 12/11/2022] Open
Abstract
Circulating free tumor DNA (ctDNA) is DNA released from necrotic or apoptotic tumor cells into the bloodstream. Absolute levels of ctDNA, as well as genetic mutations and epigenetic changes detected in ctDNA are useful biomarkers of tumor biology, progression and response to therapy in many tumor types and recent evidence suggests they may be useful in hepatocellular carcinoma (HCC). ctDNA detected in blood, therefore, offers a minimally invasive, easily repeated 'liquid biopsy' of cancer, providing real-time dynamic analysis of tumor behavior and treatment response that could revolutionize both clinical and research practice in HCC. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in HCC.
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Affiliation(s)
- Jessica A Howell
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK.,Centre for Population Health, MacFarlane-Burnet Institute, Melbourne, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia.,Department of Hepatology, St Mary's Hospital, Imperial College, London, UK.,Centre for Population Health, MacFarlane-Burnet Institute, Melbourne, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Rohini Sharma
- Department of Oncology, Hammersmith Hospital, Imperial College, London, UK.,Department of Oncology, Hammersmith Hospital, Imperial College, London, UK
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33
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Galun D, Basaric D, Zuvela M, Bulajic P, Bogdanovic A, Bidzic N, Milicevic M. Hepatocellular carcinoma: From clinical practice to evidence-based treatment protocols. World J Hepatol 2015; 7:2274-91. [PMID: 26380652 PMCID: PMC4568488 DOI: 10.4254/wjh.v7.i20.2274] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 07/06/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant diseases in many healthcare systems. The growing number of new cases diagnosed each year is nearly equal to the number of deaths from this cancer. Worldwide, HCC is a leading cause of cancer-related deaths, as it is the fifth most common cancer and the third most important cause of cancer related death in men. Among various risk factors the two are prevailing: viral hepatitis, namely chronic hepatitis C virus is a well-established risk factor contributing to the rising incidence of HCC. The epidemic of obesity and the metabolic syndrome, not only in the United States but also in Asia, tend to become the leading cause of the long-term rise in the HCC incidence. Today, the diagnosis of HCC is established within the national surveillance programs in developed countries while the diagnosis of symptomatic, advanced stage disease still remains the characteristic of underdeveloped countries. Although many different staging systems have been developed and evaluated the Barcelona-Clinic Liver Cancer staging system has emerged as the most useful to guide HCC treatment. Treatment allocation should be decided by a multidisciplinary board involving hepatologists, pathologists, radiologists, liver surgeons and oncologists guided by personalized -based medicine. This approach is important not only to balance between different oncologic treatments strategies but also due to the complexity of the disease (chronic liver disease and the cancer) and due to the large number of potentially efficient therapies. Careful patient selection and a tailored treatment modality for every patient, either potentially curative (surgical treatment and tumor ablation) or palliative (transarterial therapy, radioembolization and medical treatment, i.e., sorafenib) is mandatory to achieve the best treatment outcome.
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Affiliation(s)
- Danijel Galun
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Dragan Basaric
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Marinko Zuvela
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Predrag Bulajic
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Aleksandar Bogdanovic
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Nemanja Bidzic
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Miroslav Milicevic
- Danijel Galun, Dragan Basaric, Marinko Zuvela, Predrag Bulajic, Aleksandar Bogdanovic, Nemanja Bidzic, Miroslav Milicevic, Clinic of Digestive Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia
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34
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Lin LL, Wang W, Chang J, Song X, Yu R, Qiu DM. Effects of Mutations of 3 Amino Acids on Hepatocellular Carcinoma. Technol Cancer Res Treat 2015; 14:262-9. [DOI: 10.1177/1533034614547455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 05/25/2014] [Indexed: 11/17/2022] Open
Abstract
In recent years, over 1000 reports have been published on the association between hepatic diseases and gene mutations which may result in pathogenic amino acids. Most of the studies focus on the hepatocellular carcinoma (HCC). The aim was to systematically examine the published literature on the association between the mutations of arginine, serine, and threonine and hepatic diseases, particularly HCC. The Biosciences information service database was systematically searched before July 10, 2012. Of the initially selected 471 publications, 112 articles were included in this study. Meta-analyses were conducted for 3 amino acids. Risk ratios were used to analyze the association between amino acids and liver diseases. We analyze the literature on the association between gene mutations and hepatic diseases, especially in patients with HCC. Full-text articles were analyzed by 4 independent researchers. Some amino acid mutations were found only in people with liver diseases—not in the general population. Arginine and threonine mutations occurred more frequently in patients with hepatic diseases, compared to the normal population. There is a statistically significant association between arginine mutations and the risk of HCC and serine mutations and the risk of HCC.
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Affiliation(s)
- Li Li Lin
- Department of Pharmacology, Wuxi Higher Health Vocational Technology School, Wuxi, China
| | - Wei Wang
- School of Phamary, Second Military Medical University, Shanghai, China
| | - Jing Chang
- Department of Pharmacology, Wuxi Higher Health Vocational Technology School, Wuxi, China
| | - XuRui Song
- School of Phamary, Second Military Medical University, Shanghai, China
| | - RuYun Yu
- Department of Pharmacology, Wuxi Higher Health Vocational Technology School, Wuxi, China
| | - Dong Min Qiu
- Department of Pharmacology, Wuxi Higher Health Vocational Technology School, Wuxi, China
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35
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Abstract
Hepatocellular carcinoma is one of the major malignant tumors in the world today. The number of new cases of the tumor increases year by year, and hepatocellular carcinoma almost always runs a fulminant course and carries an especially grave prognosis. It has a low resectability rate and a high recurrence rate after surgical intervention, and responds poorly to anticancer drugs and radiotherapy. Hepatocellular carcinoma does not have a uniform geographical distribution: rather, very high incidences occur in Eastern and Southeastern Asia and in sub-Saharan Black Africans. In these regions and populations, the tumor shows a distinct shift in age distribution toward the younger ages, seen to greatest extent in sub-Saharan Black Africans. In all populations, males are more commonly affected. The most common risk factors for hepatocellular carcinoma in resource-poor populations with a high incidence of the tumor are chronic hepatitis B virus infection and dietary exposure to the fungal hepatocarcinogen aflatoxin B1. These two causative agents act either singly or synergistically. Both the viral infection and exposure to the fungus occur from early childhood, and the tumor typically presents at an early age. Chronic hepatitis C virus infection is an important cause of hepatocellular carcinoma in resource-rich countries with a low incidence of the tumor. The infection is acquired in adulthood and hepatocellular carcinoma occurs later than it does with hepatitis B virus-induced tumors. In recent years, obesity and the metabolic syndrome have increased markedly in incidence and importance as a cause of hepatocellular carcinoma in some resource-rich regions. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. Excessive iron accumulation in hereditary hemochromatosis and dietary iron overload in the Black African population and membranous obstruction of the inferior cava cause the tumor in a few countries.
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Affiliation(s)
- Michael C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
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36
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Su YH, Lin SY, Song W, Jain S. DNA markers in molecular diagnostics for hepatocellular carcinoma. Expert Rev Mol Diagn 2014; 14:803-17. [PMID: 25098554 DOI: 10.1586/14737159.2014.946908] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is the one of the leading causes of cancer mortality in the world, mainly due to the difficulty of early detection and limited therapeutic options. The implementation of HCC surveillance programs in well-defined, high-risk populations were only able to detect about 40-50% of HCC at curative stages (Barcelona Clinic Liver Cancer stages 0 & 1) due to the low sensitivities of the current screening methods. The advance of sequencing technologies has identified numerous modifications as potential candidate DNA markers for diagnosis/surveillance. Here we aim to provide an overview of the DNA alterations that result in activation of cancer pathways known to potentially drive HCC carcinogenesis and to summarize performance characteristics of each DNA marker in the periphery (blood or urine) for HCC screening.
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Affiliation(s)
- Ying-Hsiu Su
- Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Philadelphia, PA 18902, USA
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37
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Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World J Surg Oncol 2014; 12:246. [PMID: 25085449 PMCID: PMC4121298 DOI: 10.1186/1477-7819-12-246] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 07/04/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding hepatocellular carcinoma in Tanzania, and the study area in particular. This study describes the clinicopathological profile of hepatocellular carcinoma in our local setting and highlights the challenging problems in the management of this disease. METHODS This was a retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013. RESULTS A total of 142 patients (M: F = 2.2: 1) were studied representing 4.6% of all malignancies. The median age of patients was 45 years. Hepatitis B virus infection (66.2%) and heavy alcohol consumption (60.6%) were the most frequently identified risk factors for hepatocellular carcinoma. The majority of patients (88.0%) presented late with advanced stages. HBsAg was positive in 66.2% of the patients and Hepatitis C Virus antibody in 16.9%. Thirteen (9.2%) patients tested positive for HIV infection. Most patients (52.8%) had both right and left lobe involvement. The trabecular pattern (47.9%) was the most frequent histopathological type. None of patients had curative therapy because of the advanced nature of the disease. Coagulopathy (45.7%) was the most common complications. The overall mortality rate was 46.5% and it was significantly associated with comorbidity, HIV positivity, CD4+ count <200 cells/μl, high histological grade, advanced stage of the tumor, presence of distant metastases at the time of diagnosis, and associated complications (P < 0.001). The overall median duration of hospital stay was 14 days. The majority of patients (71.1%) were lost to follow-up at the end of the follow-up period. CONCLUSIONS Hepatocellular carcinoma patients in this region are relatively young at diagnosis and the majority of them present late with an advanced stage and high rate of distant metastasis. Lack of awareness of the disease, poor accessibility to healthcare facilities, and lack of screening programs in this region may contribute to advanced disease at the time of diagnosis. There is a need for early detection, adequate treatment, and proper follow-up to improve treatment outcome.
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Affiliation(s)
- Hyasinta Jaka
- Department of Internal Medicine, Catholic University of Health and Allied Sciences- Bugando, P.O. Box 1464, Mwanza, Tanzania
| | - Stephen E Mshana
- Department of Microbiology & Immunology, Catholic University of Health and Allied Sciences- Bugando, P.O. Box 1464, Mwanza, Tanzania
| | - Peter F Rambau
- Department of Pathology, Catholic University of Health and Allied Sciences- Bugando, Bugando, P.O. Box 1464, Mwanza, Tanzania
| | - Nestory Masalu
- Department of Oncology, Catholic University of Health and Allied Sciences- Bugando, Bugando, P.O. Box 1464, Mwanza, Tanzania
| | - Phillipo L Chalya
- Department of Surgery, Catholic University of Health and Allied Sciences- Bugando, Bugando, P.O. Box 1464, Mwanza, Tanzania
| | - Samuel E Kalluvya
- Department of Internal Medicine, Catholic University of Health and Allied Sciences- Bugando, P.O. Box 1464, Mwanza, Tanzania
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38
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Affiliation(s)
- Felicia Wu
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; ,
| | - John D. Groopman
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205;
| | - James J. Pestka
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; ,
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39
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Fye HKS, Wright-Drakesmith C, Kramer HB, Camey S, da Costa AN, Jeng A, Bah A, Kirk GD, Sharif MIF, Ladep NG, Okeke E, Hainaut P, Taylor-Robinson SD, Kessler BM, Mendy ME. Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west African populations. PLoS One 2013; 8:e68381. [PMID: 23935864 PMCID: PMC3728326 DOI: 10.1371/journal.pone.0068381] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 05/28/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. METHODS Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. RESULTS Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. CONCLUSIONS The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance.
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Affiliation(s)
- Haddy K. S. Fye
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology - University of Oxford, Oxford, Oxfordshire, United Kingdom
- Department of Disease Control and Elimination, MRC Unit (UK) The Gambia Laboratories, Fajara, Banjul, The Gambia
| | - Cynthia Wright-Drakesmith
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology - University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Holger B. Kramer
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology - University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Suzi Camey
- Laboratory Services and Bio-bank Group, International Agency for Research on Cancer, Lyon, France
- Departamento de Estatistica, Instituto de Matematica, Universidade Federal do Rio Grande do Sul, Rio Grande, Brazil
| | - Andre Nogueira da Costa
- Laboratory Services and Bio-bank Group, International Agency for Research on Cancer, Lyon, France
| | - Adam Jeng
- Department of Disease Control and Elimination, MRC Unit (UK) The Gambia Laboratories, Fajara, Banjul, The Gambia
| | - Alasana Bah
- Department of Disease Control and Elimination, MRC Unit (UK) The Gambia Laboratories, Fajara, Banjul, The Gambia
| | - Gregory D. Kirk
- Department of Epidemiology - Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Mohamed I. F. Sharif
- Liver Unit - Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Nimzing G. Ladep
- Liver Unit - Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Edith Okeke
- Jos University Teaching Hospital, Jos, Plateau State, Nigeria
| | - Pierre Hainaut
- Laboratory Services and Bio-bank Group, International Agency for Research on Cancer, Lyon, France
- The International Prevention Research Institute, Lyon, France
| | - Simon D. Taylor-Robinson
- Liver Unit - Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Benedikt M. Kessler
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology - University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Maimuna E. Mendy
- Laboratory Services and Bio-bank Group, International Agency for Research on Cancer, Lyon, France
- Department of Disease Control and Elimination, MRC Unit (UK) The Gambia Laboratories, Fajara, Banjul, The Gambia
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40
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de Carvalho FM, de Almeida Pereira T, Gonçalves PL, Jarske RD, Pereira FEL, Louro ID. Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil. Mol Biol Rep 2013; 40:4883-7. [PMID: 23649769 DOI: 10.1007/s11033-013-2587-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Accepted: 04/29/2013] [Indexed: 01/27/2023]
Abstract
The close relationship between aflatoxins and 249ser TP53 gene mutation (AGG to AGT, Arg to Ser) in hepatocellular carcinoma (HCC) makes this mutation an indirect indicator of dietary contamination with this toxin. We have examined the prevalence of codon 249 TP53 mutation in 41 HCC and 74 liver cirrhosis (without HCC) cases diagnosed at the HUCAM University Hospital in Vitoria, Espírito Santo State, Brazil. DNA was extracted from paraffin sections and from plasma. The mutation was detected by DNA amplification, followed by restriction endonuclease digestion and confirmed by direct sequencing. DNA restriction showed 249ser mutation in 16 HCC and 13 liver cirrhosis, but sequencing confirmed mutations in only 6 HCC and 1 liver cirrhosis. In addition, sequencing revealed 4 patients with mutations at codon 250 (250ser and 250leu) in HCC cases. The prevalence of TP53 mutation was 10/41 (24.3%) in HCC and 1/74 (1.4%) in liver cirrhosis. No relationship between the presence of mutations and the etiology of HCC was observed. TP53 exon 7 mutations, which are related to aflatoxins exposure, were found at 14.6% (249ser), 7.3% (250leu) and 2.4% (250ser) in 41 cases of HCC and 1.4% in 74 liver cirrhosis (without HCC) cases, suggesting a moderate dietary exposure to aflatoxins in the Espírito Santo State, Brazil.
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Affiliation(s)
- Fernanda Magri de Carvalho
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Centro de Ciências Humanas e Naturais, Universidade Federal do Espírito Santo, Av. Marechal Campos 1468, Campus de Maruípe, Vitória, Espírito Santo, CEP 29040-090, Brazil
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Zhao B, Shen H, Liu F, Liu S, Niu J, Guo F, Sun X. Exposure to organochlorine pesticides is an independent risk factor of hepatocellular carcinoma: a case-control study. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2012; 22:541-8. [PMID: 21915153 DOI: 10.1038/jes.2011.29] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Primary hepatocellular carcinoma (HCC) is highly prevalent in China. Although hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are considered the major risk factors, among the high-risk cohorts only a small fraction develops liver cancer. Therefore, we investigated whether organochlorine pesticide exposure contributed to HCC risk in the Xiamen population. The questionnaire database was built from 346 HCC cases and 961 healthy controls during 2007-2009. The serum levels of α-, β-, γ-, δ-HCH, 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (p,p'-DDT), (1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p'-DDE), 1,1,1-trichloro-2,2-bis (o-chlorophenyl) ethane and 1,1-dichloro-2,2-bis (p-chlorophenyl) ethane were measured by gas chromatography-tandem mass spectrometer, and statistical analysis was done using SPSS16. Significantly, we observed p,p'-DDT and p,p'-DDE, and at the first time β-HCH displayed quartile dose-dependent HCC risk trends; p,p'-DDT showed positive (i.e., synergistic) interactions with HBV, diabetes mellitus, AFB1 and polyaromatic hydrocarbon (PAH) exposure, but negative (i.e., antagonistic) interaction with heavy drinking; p,p'-DDE had positive interaction with PAH but negative interaction with HBV and p,p'-DDT; and β-HCH positively interacted with p,p'-DDT but negatively interacted with heavy drinking and diabetes. p,p'-DDT, p,p'-DDE and β-HCH were independent HCC risk factors. Because of their synergistic interactions with other factors, the high-level exposure combined with common AFB1 and HBV exposure in the investigated area may greatly enhance the risk of HCC.
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Affiliation(s)
- Benhua Zhao
- Medical College of Xiamen University, Xiamen 361005, PRC
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Abstract
Hepatocellular carcinoma (HCC) is considered to be a fatal disease because of its late diagnosis, underlying liver disease, and refractoriness to systemic treatments. Biomarkers with high sensitivity and specificity that are minimally invasive, reproducible, and easily available have important clinical utility for early diagnosis, prognostication, and pharmacodynamics evaluation. Until now, most of the circulating HCC biomarkers used in clinical practice were protein molecules. However, these biomarkers often had low sensitivity and specificity. In the past decade, circulating cell-free nucleic acids (cfNAs) have been extensively studied. We review the studies that evaluated cfNAs as circulating HCC biomarkers and discuss recent advances with regard to their diagnostic and prognostic significance.
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Affiliation(s)
- Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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43
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Villar S, Ortiz-Cuaran S, Abedi-Ardekani B, Gouas D, Nogueira da Costa A, Plymoth A, Khuhaprema T, Kalalak A, Sangrajrang S, Friesen MD, Groopman JD, Hainaut P. Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis. PLoS One 2012. [PMID: 22675488 DOI: 10.1371/-journal.pone.0037707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G → T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥ 67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.
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44
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Villar S, Ortiz-Cuaran S, Abedi-Ardekani B, Gouas D, Nogueira da Costa A, Plymoth A, Khuhaprema T, Kalalak A, Sangrajrang S, Friesen MD, Groopman JD, Hainaut P. Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis. PLoS One 2012; 7:e37707. [PMID: 22675488 PMCID: PMC3366967 DOI: 10.1371/journal.pone.0037707] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 04/23/2012] [Indexed: 01/26/2023] Open
Abstract
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G→T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.
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MESH Headings
- Adult
- Aflatoxins/adverse effects
- Aged
- Amino Acid Substitution/genetics
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/genetics
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- DNA, Neoplasm/blood
- Female
- Geography
- Hepatitis B Surface Antigens/immunology
- Hepatitis C Antibodies/immunology
- Hepatitis, Chronic/blood
- Hepatitis, Chronic/complications
- Hepatitis, Chronic/immunology
- Humans
- Liver Cirrhosis/blood
- Liver Cirrhosis/complications
- Liver Neoplasms/blood
- Liver Neoplasms/chemically induced
- Liver Neoplasms/complications
- Liver Neoplasms/genetics
- Male
- Middle Aged
- Mutation/genetics
- Thailand
- Tumor Suppressor Protein p53/genetics
- alpha-Fetoproteins/metabolism
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Affiliation(s)
| | | | | | - Doriane Gouas
- International Agency for Research on Cancer, Lyon, France
| | | | | | | | | | | | - Marlin D. Friesen
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - John D. Groopman
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Pierre Hainaut
- International Agency for Research on Cancer, Lyon, France
- International Prevention Research Institute, Lyon, France
- * E-mail:
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45
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Ewald PW, Swain Ewald HA. Infection, mutation, and cancer evolution. J Mol Med (Berl) 2012; 90:535-41. [PMID: 22476248 DOI: 10.1007/s00109-012-0891-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 03/03/2012] [Accepted: 03/07/2012] [Indexed: 01/27/2023]
Abstract
An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide infrequent opportunities for transmission, such as transmission by sexual and salivary contact. Such routes increase the intensity of natural selection for persistence within hosts, and molecular mechanisms for persistence often compromise critical barriers to oncogenesis, particularly cell cycle arrest, apoptosis, and a cap on the total number of divisions that a cell can undergo.
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Affiliation(s)
- Paul W Ewald
- Department of Biology, University of Louisville, Louisville, KY 40292, USA.
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Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis. Eur J Cancer 2012; 48:2125-36. [PMID: 22405700 DOI: 10.1016/j.ejca.2012.02.009] [Citation(s) in RCA: 211] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 02/03/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Over 4 billion people worldwide are exposed to dietary aflatoxins, which cause liver cancer (hepatocellular carcinoma, HCC) in humans. However, the population attributable risk (PAR) of aflatoxin-related HCC remains unclear. METHODS In our systematic review and meta-analysis of epidemiological studies, summary odds ratios (ORs) of aflatoxin-related HCC with 95% confidence intervals were calculated in HBV+ and HBV- individuals, as well as the general population. We calculated the PAR of aflatoxin-related HCC for each study as well as the combined studies, accounting for HBV status. RESULTS Seventeen studies with 1680 HCC cases and 3052 controls were identified from 479 articles. All eligible studies were conducted in China, Taiwan, or sub-Saharan Africa. The PAR of aflatoxin-related HCC was estimated at 17% (14-19%) overall, and higher in HBV+ (21%) than HBV- (8.8%) populations. If the one study that contributed most to heterogeneity in the analysis is excluded, the summarised OR of HCC with 95% CI is 73.0 (36.0-148.3) from the combined effects of aflatoxin and HBV, 11.3 (6.75-18.9) from HBV only and 6.37 (3.74-10.86) from aflatoxin only. The PAR of aflatoxin-related HCC increases to 23% (21-24%). The PAR has decreased over time in certain Taiwanese and Chinese populations. CONCLUSIONS In high exposure areas, aflatoxin multiplicatively interacts with HBV to induce HCC; reducing aflatoxin exposure to non-detectable levels could reduce HCC cases in high-risk areas by about 23%. The decreasing PAR of aflatoxin-related HCC reflects the benefits of public health interventions to reduce aflatoxin and HBV.
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47
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Nishida N, Goel A. Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review. Curr Genomics 2011; 12:130-7. [PMID: 21966251 PMCID: PMC3129047 DOI: 10.2174/138920211795564359] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Revised: 01/04/2011] [Accepted: 01/18/2011] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs emerge in the background of a chronic liver disease, such as chronic hepatitis and liver cirrhosis. The current understanding is that majority of HCCs evolve as a consequence of chronic inflammation and due to the presence of infection with hepatitis viruses. These underlying pathogenic stimuli subsequently induce a spectrum of genetic and epigenetic alterations in several cancer-related genes, which are involved in cell-cycle regulation, cell growth and adhesion. Such widespread genomic alterations cause disruption of normal cellular signaling and finally lead to the acquisition of a malignant phenotype in HCC. In general, the type of gene alterations, such as point mutations, deletion of chromosomal regions and abnormal methylation of gene promoters differ according to the individual targeted gene. In HCC, incidence of genetic alterations is relatively rare and is limited to a subset of few cancer-specific genes, such as the tumor suppressor p53, RB genes and oncogenes such as the CTNNB1. In contrast, epigenetic changes that involve aberrant methylation of genes and other post-transcriptional histone modifications occur far more frequently, and some of these epigenetic alterations are now being exploited for the development of molecular diagnostic signatures for HCC. In addition, recent findings of unique microRNA expression profiles also provide an evidence for the existence of novel mechanisms for gene expression regulation in HCC. In this review article, we will review the current state of knowledge on the activation of various oncogenic pathways and the inactivation of tumor suppressor pathways in HCC that result in the disruption of cancer-related gene function. In addition, we will specifically emphasize the clinical implication of some of these genetic and epigenetic alterations in the management of hepatocarcinogenesis.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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48
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Zhao B, Shen H, Liu F, Liu S, Niu J, Guo F, Sun X. Exposure to organochlorine pesticides is independent risk factor of hepatocellular carcinoma: a case--control study. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2011; 21:601-608. [PMID: 21750577 DOI: 10.1038/jes.2011.24] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Accepted: 02/24/2011] [Indexed: 05/31/2023]
Abstract
Primary hepatocellular carcinoma (HCC) is highly prevalent in China. Although hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are considered the major risk factors, among the high-risk cohorts only a small fraction develops liver cancer. Therefore, we investigated if organochlorine pesticides (OCPs) exposure contributed to HCC risk in the Xiamen population. The questionnaire database was built from 346 HCC cases and 961 healthy controls during 2007-2009. The serum levels of α-, β-, γ-, δ-HCH, p, p'-DDT, p, p'-DDE, o, p'-DDT and p, p'-DDD were measured by gas chromatography-tandem mass spectrometer and statistical analysis was done using SPSS16. Significantly, we observed p, p'-DDT, p, p'-DDE, and at first time β-HCH displayed quartile dose-dependent HCC risk trends; p, p'-DDT showed positive (i.e., synergistic) interactions with HBV, diabetes mellitus, AFB1 and polycyclic aromatic hydrocarbon (PAH) exposure, but negative (i.e., antagonistic) interaction with heavy drinking; p, p'-DDE had positive interaction with PAH but negative interaction with HBV and p, p'-DDT; and β-HCH was positively interacted with p, p'-DDT but negatively interacted with heavy drinking and diabetes. p, p'-DDT, p, p'-DDE and β-HCH were independent HCC risk factors. Because of their synergistic interactions with other factors, the high level exposure combined with common AFB1 and HBV exposure in the investigated area may greatly enhance the risk of HCC.
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Affiliation(s)
- Benhua Zhao
- Medical College of Xiamen University, Xiamen, PR China, 361005
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49
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Mah YH, Hsu CS, Liu CH, Liu CJ, Lai MY, Chen PJ, Chen DS, Kao JH. Serum p53 gene polymorphisms and severity of hepatitis B or C-related chronic liver diseases in Taiwan. Hepatol Int 2011; 5:814-821. [PMID: 21484135 DOI: 10.1007/s12072-010-9248-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Accepted: 12/29/2010] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND AIMS Polymorphisms of p53 gene are known to play an important role in hepatocarcinogenesis. We aimed to investigate the impact of p53 polymorphisms on disease progression by evaluating their prevalence among chronic hepatitis B (CHB) or hepatitis C (CHC) patients with different stages of liver disease. METHODS A total of 215 CHB, 108 CHC patients with different stages of liver disease and 49 healthy controls were consecutively enrolled. The codon 249 p53 mutations as well as codon 72 polymorphisms were assayed by molecular methods, and their prevalence among the enrolled subjects was evaluated. RESULTS All patients and controls had codon 249 wild-type sequences. Among codon 72 sequences, Pro/Pro allele frequency of Hepatitis B-related HCC (31.4%), cirrhosis (26.9%), HBV carriers (26.3%), hepatitis C-related cirrhosis (39.1%), and CHC patients (24%) were higher than that of healthy controls (18.4%). After adjustment for sex and age, codon 72 mutant and mixed type were associated with a higher likelihood of asymptomatic carrier state than those with wild type in CHB patients [odd ratio (OR): 2.53, 95% confidence interval (CI) 1.06-6.03, P = 0.037]. However, the prevalence of codon 72 mutant and mixed type were comparable with wild type among CHC patients with HCC (OR 0.70, 95% CI 0.28-1.72, P = 0.433). CONCLUSIONS Although serum 249(serine) p53 mutation is rarely found in Taiwanese patients, HBV carriers have a higher prevalence of codon 72 mutants than patients with much severe liver diseases or HCV infection, which implies that codon 72 mutants may affect at an earlier stage of HBV infection. Further studies are necessary to delineate the interactions of p53 mutations with HBV infection.
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Affiliation(s)
- Yone-Han Mah
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan,
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Ananthakrishnan A, Gogineni V, Saeian K. Epidemiology of primary and secondary liver cancers. Semin Intervent Radiol 2011; 23:47-63. [PMID: 21326720 DOI: 10.1055/s-2006-939841] [Citation(s) in RCA: 144] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary liver cancer is the sixth most common cancer worldwide with a wide geographic distribution. The incidence of primary liver cancer is increasing and there is still a higher prevalence in developing countries. Early recognition remains an obstacle and lack of it results in poor outcomes for hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, and cholangiocarcinoma. The most common risk factors associated with HCC are hepatitis B and chronic hepatitis C infections, alcohol use, smoking, and aflatoxin exposure. Emerging risk factors such as obesity might play an important role in the future because of the increasing prevalence of this condition.
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Affiliation(s)
- Ashwin Ananthakrishnan
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin
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