Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma.

Siyuan He, Yuchen Jiao, Chunfeng Qu, Yi-Xin Zeng, Zongtang Sun, Zhihua Liu, Jianqiang Cai, Xiaoyue Wang, Zhiyuan Wu, Xiaoyan Chen, Weilong Zhang, Ying Zhang, Nengjin Wang, Hongwei Zheng, Peiqing Ma, Ling-Ling Lu, Hong Zhao, Qifeng Wu, Mengya Zang, Huan He

Journal: Gastroenterology 2017;153(1):249-262.e2

PMID: 28363643

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND & AIMS

Dietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen.

METHODS

We obtained HCC tumor tissues and matched non-tumor liver tissues from 49 patients, collected from 1990 through 2016, at the Qidong Liver Cancer Hospital Institute in China-a high-risk region for aflatoxin exposure (38.2% of food samples test positive for aflatoxin contamination). Somatic variants were identified using GATK Best Practices Pipeline. We validated part of the mutations from whole-genome sequencing and whole-exome sequencing by Sanger sequencing. We also analyzed genomes of 1072 HCCs, obtained from 5 datasets from China, the United States, France, and Japan. Mutations in 49 aflatoxin-associated HCCs and 1072 HCCs from other regions were analyzed using the Wellcome Trust Sanger Institute mutational signatures framework with non-negative matrix factorization. The mutation landscape and mutational signatures from the aflatoxin-associated HCC and HCC samples from general population were compared. We identified genetic features of aflatoxin-associated HCC, and used these to identify aflatoxin-associated HCCs in datasets from other regions. Tumor samples were analyzed by immunohistochemistry to determine microvessel density and levels of CD34 and CD274 (PD-L1).

RESULTS

Aflatoxin-associated HCCs frequently contained C>A transversions, the sequence motif GCN, and strand bias. In addition to previously reported mutations in TP53, we found frequent mutations in the adhesion G protein-coupled receptor B1 gene (ADGRB1), which were associated with increased capillary density of tumor tissue. Aflatoxin-associated HCC tissues contained high-level potential mutation-associated neoantigens, and many infiltrating lymphocytes and tumors cells that expressed PD-L1, compared to HCCs not associated with aflatoxin. Of the HCCs from China, 9.8% contained the aflatoxin-associated genetic features, whereas 0.4%-3.5% of HCCs from other regions contained these genetic features.

CONCLUSIONS

We identified specific genetic and mutation features of HCCs associated with aflatoxin exposure, including mutations in ADGRB1, compared to HCCs from general populations. We associated these mutations with increased vascularization and expression of PD-L1 in HCC tissues. These findings might be used to identify patients with HCC due to aflatoxin exposure, and select therapies.

Address: State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Collaborative Innovation Center for Cancer Medicine; Third Hospital, Peking University, Beijing, China.; State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Department of Abdominal Surgical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Qidong People's Hospital and Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China.; Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.; National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, China. Electronic address: [email protected].; State Key Lab of Molecular Oncology, Immunology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleges, Beijing, China. Electronic address: [email protected].; State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Collaborative Innovation Center for Cancer Medicine, Beijing, China. Electronic address: [email protected].

DOI: 10.1053/j.gastro.2017.03.024