Abstract
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.
List of abbreviations
- AFB1
- aflatoxin B1
- AFB1sig
- Extension of AFB1sigG>N to all 96 trinucleotide contexts by setting A > N mutations to 0
- AFB1sigG>N
- 1st NMF-extracted signature from G>N mutations in trinucleotide context experimental data and likely strongly aflatoxin exposed HCCs
- AFsig2
- Extension of AFsig2G>N to all 96 trinucleotide contexts by setting A > N mutations to 0
- AFsig2G>N
- 2nd NMF-extracted signature from G>N mutations in trinucleotide context experimental data and likely strongly aflatoxin exposed HCCs
- HbsAg
- hepatitis B surface antigen
- HCC
- hepatocellular carcinoma
- HepG2
- a human hepatoblastoma-derived cell line used in this study
- HepaRG
- a human HCC-derived cell line that was differentiated to cells resembling hepatocytes
- IARC
- International Agency for Research on Cancer
- IC50
- half maximal inhibitory concentration
- NMF
- nonnegative matrix factorization
- PC1
- principal component 1
- PCA
- principal components analysis
- TCGA
- The Cancer Genome Atlas project (https://cancergenome.nih.gov/)
- WES
- whole-exome sequencing
- WGS
- whole-genome sequencing