Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma

Zhang, Weilong; He, Huan; Zang, Meirong; Wu, Qifeng; Zhao, Hong; Lu, Ling; Ma, Peiqing; Zheng, Hongwei; Wang, Neng-Jin; Zhang, Ying; He, Siyuan; Chen, Xiaoyan; Wu, Zhiyuan; Wang, Xiaoyue; Cai, Jianqiang; Liu, Zhihua; Sun, Zhi‐Jun; Zeng, Yi Xin; Qu, Chunfeng; Jiao, Yuchen

doi:10.1053/j.gastro.2017.03.024

Cited by 103 publications

(103 citation statements)

References 42 publications

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“…One of aflatoxins degradation products, the metabolite exo-epoxide, forms a covalent bond with guanyl N7 (AFB1-N7-Gua), ultimately leading to G>T mutations during replication. Consistently, signature 24 has previously been found in a subset of liver cancers (Chawanthayatham et al, 2017;Zhang et al, 2017), but has not been reported for other cancer entities. We therefore tested, if the observed enrichment of signature 24 was solely introduced by a strong mutagenic effect in the liver.…”

Section: Aflatoxin Mutational Signature In Organs Of the Dietary Tractsupporting

confidence: 82%

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

Muyas

Zapata

Guigó

et al. 2019

Preprint

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Background: Mosaic mutations acquired during early embryogenesis can lead to severe earlyonset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues.Results: Using RNA sequencing data from the Genotype-Tissue Expression (GTEx) cohort comprising 49 normal tissues and 570 individuals, we found that new-borns on average harbour 0.5 -1 EMMs in the exome affecting multiple organs (1.3230 x 10 -8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multiindividual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. Conclusion:In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.

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Section: Aflatoxin Mutational Signature In Organs Of the Dietary Tractsupporting

confidence: 82%

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

Muyas

Zapata

Guigó

et al. 2019

Preprint

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“…Aflatoxins are common contaminates of staple foods and have been found to be carcinogenic in many animal species, including humans . Aflatoxin exposure is clustered in high‐risk regions, where the combination of humid weather and improper food storage conditions expose the majority of the local population to aflatoxins, significantly increasing the incidence of liver cancer . The identification and removal of this risk factor has substantially decreased the incidence of liver cancer in young adults, suggesting the importance of controlling aflatoxin as a preventive measure .…”

Section: Discussionmentioning

confidence: 99%

“…45 Aflatoxin exposure is clustered in high-risk regions, where the combination of humid weather and improper food storage conditions expose the majority of the local population to aflatoxins, significantly increasing the incidence of liver cancer. 9 The identification and removal of this risk factor has substantially decreased the incidence of liver cancer in young adults, suggesting the importance of controlling aflatoxin as a preventive measure. 46 Tobacco smoking remains a severe public health concern in China, despite the implementation of tobacco control policies since the signing of the WHO Framework Convention on Tobacco Control in 2003.…”

Section: Discussionmentioning

confidence: 99%

“…3 Etiologies underlying liver cancer have been extensively investigated in the past decade. [6][7][8][9] Hepatitis virus infections, including hepatitis B virus (HBV) and hepatitis C virus (HCV), have been identified as major contributors to liver cancer. 8,10 Accordingly, the Chinese government has initiated measures to combat the hepatitis epidemic.…”

Section: Introductionmentioning

confidence: 99%

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Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China

et al. 2019

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Background Liver cancer is a commonly diagnosed malignancy in China. The etiologies of liver cancer are widely known, although studies on temporal trends in liver cancer caused by specific etiologies are rare. Methods Data on the incidence and mortality of liver cancer were retrieved from the Global Burden of Diseases Study 2017. The estimated annual percentage change (EAPC) was used to quantify temporal trends in the age‐standardized incidence rate (ASIR) and the age‐standardized mortality rate (ASMR) of liver cancer from 1990 to 2017. Results Nationwide, the number of incident cases of liver cancer increased from 258 000 in 1990 to 515 900 in 2017. The ASIR decreased from 27.16 per 100 000 to 26.04 per 100 000 during this period, with an EAPC of −0.64 (95% confidence interval [CI] −0.84, −0.44). The number of deaths increased from 245 300 in 1990 to 418 200 in 2017, and the ASMR decreased from 26.72 to 21.30 (EAPC = −1.16, 95% CI −1.35, −0.97). The most pronounced decreases in the ASIR and ASMR were observed in liver cancer due to hepatitis B and in people aged 15‐49 years. Conclusions Since the extensive efforts for prevention of hepatitis B virus infection, the incidence of liver cancer due to hepatitis B has significantly decreased. However, liver cancer due to hepatitis C, NASH, and other causes remains a major public health concern. Additional preventive strategies tailored to liver cancer are needed to further reduce its disease burden in China.

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“…In addition, while the current paper was in review, a publication on HCCs from Qidong County, a region of known aflatoxin exposure, extracted a signature similar to COSMIC Signature 24 from HCC somatic mutations (Zhang et al 2017).…”

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confidence: 99%

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

Teoh

et al. 2017

Genome Res.

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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.

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Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma

Cited by 103 publications

References 42 publications

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China

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

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