Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis

Abstract Background Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in o...

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Autores principales:	Alejandro A. Schäffer, Dana A. Dominguez, Lesley M. Chapman, E. Michael Gertz, Anuradha Budhu, Marshonna Forgues, Jittiporn Chaisaingmongkol, Siritida Rabibhadana, Benjarath Pupacdi, Xiaolin Wu, Enkhjargal Bayarsaikhan, Curtis C. Harris, Mathuros Ruchirawat, Eytan Ruppin, Xin Wei Wang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Liver cancer Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Adeno-associated virus Virus integration Viral oncogenesis Biotechnology TP248.13-248.65 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/112941e99568473c8c4542fa2d87f042
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spelling	oai:doaj.org-article:112941e99568473c8c4542fa2d87f0422021-11-14T12:26:52ZIntegration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis10.1186/s12864-021-08098-91471-2164https://doaj.org/article/112941e99568473c8c4542fa2d87f0422021-11-01T00:00:00Zhttps://doi.org/10.1186/s12864-021-08098-9https://doaj.org/toc/1471-2164Abstract Background Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3’ end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. Results We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. Conclusions Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.Alejandro A. SchäfferDana A. DominguezLesley M. ChapmanE. Michael GertzAnuradha BudhuMarshonna ForguesJittiporn ChaisaingmongkolSiritida RabibhadanaBenjarath PupacdiXiaolin WuEnkhjargal BayarsaikhanCurtis C. HarrisMathuros RuchirawatEytan RuppinXin Wei WangBMCarticleLiver cancerHepatocellular carcinomaIntrahepatic cholangiocarcinomaAdeno-associated virusVirus integrationViral oncogenesisBiotechnologyTP248.13-248.65GeneticsQH426-470ENBMC Genomics, Vol 22, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Liver cancer Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Adeno-associated virus Virus integration Viral oncogenesis Biotechnology TP248.13-248.65 Genetics QH426-470
spellingShingle	Liver cancer Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Adeno-associated virus Virus integration Viral oncogenesis Biotechnology TP248.13-248.65 Genetics QH426-470 Alejandro A. Schäffer Dana A. Dominguez Lesley M. Chapman E. Michael Gertz Anuradha Budhu Marshonna Forgues Jittiporn Chaisaingmongkol Siritida Rabibhadana Benjarath Pupacdi Xiaolin Wu Enkhjargal Bayarsaikhan Curtis C. Harris Mathuros Ruchirawat Eytan Ruppin Xin Wei Wang Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
description	Abstract Background Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3’ end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. Results We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. Conclusions Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.
format	article
author	Alejandro A. Schäffer Dana A. Dominguez Lesley M. Chapman E. Michael Gertz Anuradha Budhu Marshonna Forgues Jittiporn Chaisaingmongkol Siritida Rabibhadana Benjarath Pupacdi Xiaolin Wu Enkhjargal Bayarsaikhan Curtis C. Harris Mathuros Ruchirawat Eytan Ruppin Xin Wei Wang
author_facet	Alejandro A. Schäffer Dana A. Dominguez Lesley M. Chapman E. Michael Gertz Anuradha Budhu Marshonna Forgues Jittiporn Chaisaingmongkol Siritida Rabibhadana Benjarath Pupacdi Xiaolin Wu Enkhjargal Bayarsaikhan Curtis C. Harris Mathuros Ruchirawat Eytan Ruppin Xin Wei Wang
author_sort	Alejandro A. Schäffer
title	Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
title_short	Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
title_full	Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
title_fullStr	Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
title_full_unstemmed	Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis
title_sort	integration of adeno-associated virus (aav) into the genomes of most thai and mongolian liver cancer patients does not induce oncogenesis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/112941e99568473c8c4542fa2d87f042
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Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis

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