RT Journal Article
SR Electronic
T1 Genome-scale mutational signatures of aflatoxin in cells, mice and human tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 130179
DO 10.1101/130179
A1 Mi Ni Huang
A1 Willie Yu
A1 Wei Wei Teoh
A1 Maude Ardin
A1 Apinya Jusakul
A1 Alvin Ng
A1 Arnoud Boot
A1 Behnoush Abedi-Ardekani
A1 Stephanie Villar
A1 Swe Swe Myint
A1 Rashidah Othman
A1 Song Ling Poon
A1 Adriana Heguy
A1 Magali Olivier
A1 Monica Hollstein
A1 Patrick Tan
A1 Bin Tean Teh
A1 Kanaga Sabapathy
A1 Jiri Zavadil
A1 Steven G. Rozen
YR 2017
UL http://biorxiv.org/content/early/2017/04/26/130179.abstract
AB Aflatoxin B1 (AFB1) is a mutagen and IARC Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here we present the first whole genome data on the mutational signatures of AFB1 exposure from a total of > 40,000 mutations in four experimental systems: two different human cell lines, and in liver tumors in wild-type mice and in mice that carried a hepatitis B surface antigen transgene – this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly-sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.AFB1aflatoxin B1AFB1sigExtension of AFB1sigG>N to all 96 trinucleotide contexts by setting A > N mutations to 0AFB1sigG>N1st NMF-extracted signature from G>N mutations in trinucleotide context experimental data and likely strongly aflatoxin exposed HCCsAFsig2Extension of AFsig2G>N to all 96 trinucleotide contexts by setting A > N mutations to 0AFsig2G>N2nd NMF-extracted signature from G>N mutations in trinucleotide context experimental data and likely strongly aflatoxin exposed HCCsHbsAghepatitis B surface antigenHCChepatocellular carcinomaHepG2a human hepatoblastoma-derived cell line used in this studyHepaRGa human HCC-derived cell line that was differentiated to cells resembling hepatocytesIARCInternational Agency for Research on CancerIC50half maximal inhibitory concentrationNMFnonnegative matrix factorizationPC1principal component 1PCAprincipal components analysisTCGAThe Cancer Genome Atlas project (https://cancergenome.nih.gov/)WESwhole-exome sequencingWGSwhole-genome sequencing