TY - JOUR T1 - Genome-scale mutational signatures of aflatoxin in cells, mice and human tumors JF - bioRxiv DO - 10.1101/130179 SP - 130179 AU - Mi Ni Huang AU - Willie Yu AU - Wei Wei Teoh AU - Maude Ardin AU - Apinya Jusakul AU - Alvin Ng AU - Arnoud Boot AU - Behnoush Abedi-Ardekani AU - Stephanie Villar AU - Swe Swe Myint AU - Rashidah Othman AU - Song Ling Poon AU - Adriana Heguy AU - Magali Olivier AU - Monica Hollstein AU - Patrick Tan AU - Bin Tean Teh AU - Kanaga Sabapathy AU - Jiri Zavadil AU - Steven G. Rozen Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/26/130179.abstract N2 - 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 ER -