Mutational spectra of aflatoxin B 1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma
Aflatoxin B (AFB ) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB -DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate...
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creator | Chawanthayatham, Supawadee Valentine, 3rd, Charles C Fedeles, Bogdan I Fox, Edward J Loeb, Lawrence A Levine, Stuart S Slocum, Stephen L Wogan, Gerald N Croy, Robert G Essigmann, John M |
description | Aflatoxin B
(AFB
) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB
-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB
using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB
exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (C
C; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB
exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB
, and, as such, is an early detection metric for AFB
-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis. |
doi_str_mv | 10.1073/pnas.1700759114 |
format | Article |
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(AFB
) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB
-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB
using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB
exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (C
C; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB
exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB
, and, as such, is an early detection metric for AFB
-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1700759114</identifier><identifier>PMID: 28351974</identifier><language>eng</language><publisher>United States</publisher><subject>Aflatoxin B1 - genetics ; Aflatoxin B1 - toxicity ; Animals ; Biomarkers - metabolism ; Carcinogenesis - chemically induced ; Carcinogenesis - genetics ; Carcinogenesis - pathology ; Carcinoma, Hepatocellular - chemically induced ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; DNA Adducts - genetics ; DNA Adducts - toxicity ; Female ; Humans ; Liver Neoplasms - chemically induced ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mutation</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2017-04, Vol.114 (15), p.E3101</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1504-3752498f6f0c4c9d2f98a9c0ea485f88a53e4ccf799000df6ac83a07396d66823</citedby><cites>FETCH-LOGICAL-c1504-3752498f6f0c4c9d2f98a9c0ea485f88a53e4ccf799000df6ac83a07396d66823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28351974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chawanthayatham, Supawadee</creatorcontrib><creatorcontrib>Valentine, 3rd, Charles C</creatorcontrib><creatorcontrib>Fedeles, Bogdan I</creatorcontrib><creatorcontrib>Fox, Edward J</creatorcontrib><creatorcontrib>Loeb, Lawrence A</creatorcontrib><creatorcontrib>Levine, Stuart S</creatorcontrib><creatorcontrib>Slocum, Stephen L</creatorcontrib><creatorcontrib>Wogan, Gerald N</creatorcontrib><creatorcontrib>Croy, Robert G</creatorcontrib><creatorcontrib>Essigmann, John M</creatorcontrib><title>Mutational spectra of aflatoxin B 1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Aflatoxin B
(AFB
) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB
-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB
using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB
exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (C
C; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB
exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB
, and, as such, is an early detection metric for AFB
-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis.</description><subject>Aflatoxin B1 - genetics</subject><subject>Aflatoxin B1 - toxicity</subject><subject>Animals</subject><subject>Biomarkers - metabolism</subject><subject>Carcinogenesis - chemically induced</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - pathology</subject><subject>Carcinoma, Hepatocellular - chemically induced</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>DNA Adducts - genetics</subject><subject>DNA Adducts - toxicity</subject><subject>Female</subject><subject>Humans</subject><subject>Liver Neoplasms - chemically induced</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0EoqWwZof8A2nHiRPbS6h4SUVsYB1NHVs1uHFkJ1X5e1KVx-pu7rmaOYRcM5gzEMWiazHNmQAQpWKMn5ApA8Wyiis4JVOAXGSS53xCLlL6AABVSjgnk1wWJVOCT0l4GXrsXWjR09QZ3UekwVK0Hvuwdy29o4yOsXO7QE3qce1d2tC1C1uMnyamQ9vsu5CGaKgNkW6GLbZ0Y7pxQBvvB4-RaozatSNzSc4s-mSufnJG3h_u35ZP2er18Xl5u8o0K4FnhShzrqStLGiuVZNbJVFpMMhlaaXEsjBcayuUGr9qbIVaFjgaUVVTVTIvZmRx3NUxpBSNrbvoxpO_agb1QV19UFf_qxuJmyPRDeutaf76v66Kb6A0bBM</recordid><startdate>20170411</startdate><enddate>20170411</enddate><creator>Chawanthayatham, Supawadee</creator><creator>Valentine, 3rd, Charles C</creator><creator>Fedeles, Bogdan I</creator><creator>Fox, Edward J</creator><creator>Loeb, Lawrence A</creator><creator>Levine, Stuart S</creator><creator>Slocum, Stephen L</creator><creator>Wogan, Gerald N</creator><creator>Croy, Robert G</creator><creator>Essigmann, John M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20170411</creationdate><title>Mutational spectra of aflatoxin B 1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma</title><author>Chawanthayatham, Supawadee ; Valentine, 3rd, Charles C ; Fedeles, Bogdan I ; Fox, Edward J ; Loeb, Lawrence A ; Levine, Stuart S ; Slocum, Stephen L ; Wogan, Gerald N ; Croy, Robert G ; Essigmann, John M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1504-3752498f6f0c4c9d2f98a9c0ea485f88a53e4ccf799000df6ac83a07396d66823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aflatoxin B1 - genetics</topic><topic>Aflatoxin B1 - toxicity</topic><topic>Animals</topic><topic>Biomarkers - metabolism</topic><topic>Carcinogenesis - chemically induced</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - pathology</topic><topic>Carcinoma, Hepatocellular - chemically induced</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>DNA Adducts - genetics</topic><topic>DNA Adducts - toxicity</topic><topic>Female</topic><topic>Humans</topic><topic>Liver Neoplasms - chemically induced</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Mice, Inbred C57BL</topic><topic>Mutation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chawanthayatham, Supawadee</creatorcontrib><creatorcontrib>Valentine, 3rd, Charles C</creatorcontrib><creatorcontrib>Fedeles, Bogdan I</creatorcontrib><creatorcontrib>Fox, Edward J</creatorcontrib><creatorcontrib>Loeb, Lawrence A</creatorcontrib><creatorcontrib>Levine, Stuart S</creatorcontrib><creatorcontrib>Slocum, Stephen L</creatorcontrib><creatorcontrib>Wogan, Gerald N</creatorcontrib><creatorcontrib>Croy, Robert G</creatorcontrib><creatorcontrib>Essigmann, John M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chawanthayatham, Supawadee</au><au>Valentine, 3rd, Charles C</au><au>Fedeles, Bogdan I</au><au>Fox, Edward J</au><au>Loeb, Lawrence A</au><au>Levine, Stuart S</au><au>Slocum, Stephen L</au><au>Wogan, Gerald N</au><au>Croy, Robert G</au><au>Essigmann, John M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutational spectra of aflatoxin B 1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2017-04-11</date><risdate>2017</risdate><volume>114</volume><issue>15</issue><spage>E3101</spage><pages>E3101-</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Aflatoxin B
(AFB
) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB
-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB
using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB
exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (C
C; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB
exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB
, and, as such, is an early detection metric for AFB
-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis.</abstract><cop>United States</cop><pmid>28351974</pmid><doi>10.1073/pnas.1700759114</doi><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
subjects | Aflatoxin B1 - genetics Aflatoxin B1 - toxicity Animals Biomarkers - metabolism Carcinogenesis - chemically induced Carcinogenesis - genetics Carcinogenesis - pathology Carcinoma, Hepatocellular - chemically induced Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology DNA Adducts - genetics DNA Adducts - toxicity Female Humans Liver Neoplasms - chemically induced Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Male Mice Mice, Inbred C3H Mice, Inbred C57BL Mutation |
title | Mutational spectra of aflatoxin B 1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma |
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