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Article: Targeted genomic profiling identifies frequent deleterious mutations in FAT4 and TP53 genes in HBV-associated hepatocellular carcinoma

TitleTargeted genomic profiling identifies frequent deleterious mutations in FAT4 and TP53 genes in HBV-associated hepatocellular carcinoma
Authors
KeywordsCustomized therapies
Deleterious mutations
Gene silencing
Hepatocellular carcinoma
Targeted sequencing
Issue Date2019
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmccancer/
Citation
BMC Cancer, 2019, v. 19, article no. 789 How to Cite?
AbstractBackground: Hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV-associated HCC pathogenesis is still unclear. Genetic alterations in cancer-related genes have been linked to many human cancers. Here, we aimed to explore genetic alterations in selected cancer-related genes in patients with HBV-associated HCC. Methods: Targeted sequencing was used to analyze six cancer-related genes (PIK3CA, TP53, FAT4, IRF2, HNF4α and ARID1A) in eight pairs of HBV-associated HCC tumors and their adjacent non-tumor tissues. Sanger sequencing, quantitative PCR, Western-blotting and RNAi-mediated gene knockdown were used to further validate findings. Results: Targeted sequencing revealed thirteen non-synonymous mutations, of which 9 (69%) were found in FAT4 and 4 (31%) were found in TP53 genes. Non-synonymous mutations were not found in PIK3CA, IRF2, HNF4α and ARID1A. Among these 13 non-synonymous mutations, 12 (8 in FAT4 and 4 in TP53) were predicted to have deleterious effect on protein function by in silico analysis. For TP53, Y220S, R249S and P250R non-synonymous mutations were solely identified in tumor tissues. Further expression profiling of FAT4 and TP53 on twenty-eight pairs of HCC tumor and non-tumor tissues confirmed significant downregulation of both genes in HCC tumors compared with their non-tumor counterparts (P < 0.001 and P < 0.01, respectively). Functional analysis using RNAi-mediated knockdown of FAT4 revealed an increased cancer cell growth and proliferation, suggesting the putative tumor suppressor role of FAT4 in HCC. Conclusions: This study highlights the importance of FAT4 and TP53 in HCC pathogenesis and identifies new genetic variants that may have potentials for development of precise therapy for HCC.
Persistent Identifierhttp://hdl.handle.net/10722/275109
ISSN
2023 Impact Factor: 3.4
2023 SCImago Journal Rankings: 1.087
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHuang, FY-
dc.contributor.authorWong, DKH-
dc.contributor.authorTsui, VWM-
dc.contributor.authorSeto, WK-
dc.contributor.authorMak, LY-
dc.contributor.authorCheung, TT-
dc.contributor.authorLai, KKY-
dc.contributor.authorYuen, MF-
dc.date.accessioned2019-09-10T02:35:38Z-
dc.date.available2019-09-10T02:35:38Z-
dc.date.issued2019-
dc.identifier.citationBMC Cancer, 2019, v. 19, article no. 789-
dc.identifier.issn1471-2407-
dc.identifier.urihttp://hdl.handle.net/10722/275109-
dc.description.abstractBackground: Hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV-associated HCC pathogenesis is still unclear. Genetic alterations in cancer-related genes have been linked to many human cancers. Here, we aimed to explore genetic alterations in selected cancer-related genes in patients with HBV-associated HCC. Methods: Targeted sequencing was used to analyze six cancer-related genes (PIK3CA, TP53, FAT4, IRF2, HNF4α and ARID1A) in eight pairs of HBV-associated HCC tumors and their adjacent non-tumor tissues. Sanger sequencing, quantitative PCR, Western-blotting and RNAi-mediated gene knockdown were used to further validate findings. Results: Targeted sequencing revealed thirteen non-synonymous mutations, of which 9 (69%) were found in FAT4 and 4 (31%) were found in TP53 genes. Non-synonymous mutations were not found in PIK3CA, IRF2, HNF4α and ARID1A. Among these 13 non-synonymous mutations, 12 (8 in FAT4 and 4 in TP53) were predicted to have deleterious effect on protein function by in silico analysis. For TP53, Y220S, R249S and P250R non-synonymous mutations were solely identified in tumor tissues. Further expression profiling of FAT4 and TP53 on twenty-eight pairs of HCC tumor and non-tumor tissues confirmed significant downregulation of both genes in HCC tumors compared with their non-tumor counterparts (P < 0.001 and P < 0.01, respectively). Functional analysis using RNAi-mediated knockdown of FAT4 revealed an increased cancer cell growth and proliferation, suggesting the putative tumor suppressor role of FAT4 in HCC. Conclusions: This study highlights the importance of FAT4 and TP53 in HCC pathogenesis and identifies new genetic variants that may have potentials for development of precise therapy for HCC.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmccancer/-
dc.relation.ispartofBMC Cancer-
dc.rightsBMC Cancer. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCustomized therapies-
dc.subjectDeleterious mutations-
dc.subjectGene silencing-
dc.subjectHepatocellular carcinoma-
dc.subjectTargeted sequencing-
dc.titleTargeted genomic profiling identifies frequent deleterious mutations in FAT4 and TP53 genes in HBV-associated hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailHuang, FY: fungyu@hkucc.hku.hk-
dc.identifier.emailWong, DKH: danywong@hku.hk-
dc.identifier.emailSeto, WK: wkseto@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.emailYuen, MF: mfyuen@hku.hk-
dc.identifier.authorityWong, DKH=rp00492-
dc.identifier.authoritySeto, WK=rp01659-
dc.identifier.authorityCheung, TT=rp02129-
dc.identifier.authorityYuen, MF=rp00479-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12885-019-6002-9-
dc.identifier.pmid31395065-
dc.identifier.pmcidPMC6686555-
dc.identifier.scopuseid_2-s2.0-85070460803-
dc.identifier.hkuros304370-
dc.identifier.hkuros302766-
dc.identifier.volume19-
dc.identifier.spagearticle no. 789-
dc.identifier.epagearticle no. 789-
dc.identifier.isiWOS:000480478100003-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1471-2407-

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