Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors

Abstract

Aflatoxin B1 (AFB1) is a mutagen and IARC (International Agency for Research on Cancer) 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, 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.

The Repertoire of Mutational Signatures in Human Cancer

“…Thus, larger datasets may be required to robustly characterise their mutational signatures. Nevertheless, the results outlined here indicate that signatures with many similarities and some differences can be found by different mathematical approaches, and that these are confirmed in many different ways, including experimentally elucidated signatures 22,31,38,41,42,54,[56][57][58][59][60][61][62] and the observation of tumors dominated by a single signature (https://www.synapse.org/#!Synapse:syn12016215) This analysis includes almost all publicly available exome and whole-genome cancer sequences, amounting in aggregate to 23,829 cancers of most cancer types. Some rare or geographically restricted signatures may not have been captured and signatures of therapeutic mutagenic exposures have not been exhaustively explored.…”

Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans

“…Various diet-related and iatrogenic exposures contribute to human cancer burden, involving, for instance, food contaminants (aflatoxin B1 [AFB1]) or alternative medicines (aristolochic acid [AA]) with well-documented mutagenic properties; AFB1 induces predominantly C:G > A:T and AA generates T:A > A:T transversions. These characteristic mutations, arising in preferred sequence contexts, allowed unequivocal association of exposure to AFB1 or AA with specific subtypes of hepatobiliary or urological cancers (Poon et al 2013;Meier et al 2014;Scelo et al 2014;JelakovicĆ et al 2015;Hoang et al 2016;Chawanthayatham et al 2017;Huang et al 2017;Ng et al 2017;Zhang et al 2017).…”

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

“…The WDPMs harbored distinct mutations in EHD1, FBXO10, CHD5, MAGED1, ATM, and TP73 genes either in all five or at least four out of five WDPM cases. The COSMIC mutational signature 24 has been shown to be commonly found in certain liver cancers with exposure to carcinogen such as aflatoxin 22 . However, these WDPMs were incidental findings during surgery and any prior exposure to carcinogens (either aflatoxin or asbestos) is extremely unlikely.…”