Genome-wide AFB1-induced mutational signature in cells, mice and human tumors – implications for molecular epidemiology
Willie YU, Duke-NUS Medical School Singaproe, Singapore
HUANG M. 1, 2
, TEOH W. 3
, ARDIN M. 4
, ABEDI-ARDEKANI B. 5
, VILLAR S. 4
, JUSAKUL A. 2, 6
, MYINT S. 6
, OTHMAN R. 3
, MAGALI O. 4
, HOLLSTEIN M. 4
, TEH B. 2, 6
, SABAPATHY K. 3
, ZAVADIL J. 4
, ROZEN S. 1, 2
1 Centre for Computational Biology, Duke-NUS Medical School Singapore, Republic of Singapore
2 Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Republic of Singapore
3 Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Republic of Singapore
4 Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon, France
5 Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
6 Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Republic of Singapore
Purpose: Aflatoxin B1 (AFB1), a mutagen and IARC Group 1 carcinogen, causes hepatocellular carcinoma (HCC). The mutagenic effects of AFB1 on TP53 and reporter genes have been studied experimentally and in HCCs. Here we present first-of-its-kind data on the extended, genome-wide AFB1 mutagenesis using human and mouse in vivo and in vitro experimental systems.
Methods/Results: We determined genome-wide mutation patterns induced by AFB1 in two human cell-lines and a mouse model of HCC. The cell-line mutational patterns were remarkably stable across replicates, but differed somewhat between cell lines. Mutational patterns in the mouse tumors were more variable across replicates, possibly reflecting variability in the physiological clearance of the toxin in mice or random events during tumorigenesis. However, the overall pattern was consistently dominated by G>T mutations with a preference for TGC>TTC and substantial mutation enrichment on the non-transcribed strand. We next integrated these results with publicly available human HCC data and newly generated genomic HCC data from a known region of aflatoxin exposure. Like the experimental systems, the human HCCs showed high rates of G>T mutations and strong transcriptional strand bias, providing evidence that the HCCs were direct consequences of AFB1 exposure. However, they differed from the experimental systems in that the most prominent mutations were GGC>GTC. This difference may be due to exposure to other aflatoxins, to other mutagens, or to differences in biochemical processing of AFB1.
Conclusions: The experimental cell-based systems and mouse models used in our study present innovative tools allowing to determine genome-wide mutational signatures of candidate mutagenic carcinogens. We propose that the described experimental, multi-system approach can be used more broadly in support of molecular epidemiology studies aimed at cancer prevention.
Funding source: IARC Regular Budget; ITMO CANCER – INSERM Plan Cancer 2015; NIH/NIEHS 1R03ES025023-01A1; Singapore A*STAR and MOH via Duke-NUS and NMRC/CIRG/1422/2015.