TY - JOUR
T1 - Integrative genomic analysis of mouse and human hepatocellular carcinoma
AU - Dow, Michelle
AU - Pyke, Rachel M.
AU - Tsui, Brian Y.
AU - Alexandrov, Ludmil B.
AU - Nakagawa, Hayato
AU - Taniguchi, Koji
AU - Seki, Ekihiro
AU - Harismendy, Olivier
AU - Shalapour, Shabnam
AU - Karin, Michael
AU - Carter, Hannah
AU - Font-Burgada, Joan
N1 - Funding Information:
for the Promotion of Science Grant-in-Aid for Scientific Research Grant JP15K21775 (to K.T.); the “Kibou Projects” Startup Support for Young Researchers in Immunology (K.T.); the Irvington Cancer Research Institute (S.S.); a Prostate Cancer Foundation Young Investigator Award (to S.S.); and a Southern California Research Center for ALPD and Cirrhosis grant (to S.S.). M.K. holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases endowed by the University of California San Diego School of Medicine. The results published here are based in part upon data generated by TCGA managed by the National Cancer Institute and the National Human Genome Research Institute. Information about TCGA can be found at https://cancergenome.nih.gov/.
Funding Information:
ACKNOWLEDGMENTS. This research was supported by NIH Grants CA118165, AI043477, U01AA022614, and P42ES010337 (to M.K.), DP5-OD017937 (to H.C.), K99/R00CA191152 (to J.F.-B.), and R01DK085252 (to E.S); Moores Cancer Center Support Grant P30CA023100 (to O.H.); a grant from Bristol-Myers Squibb (to K.T.); NIH National Library of Medicine Training Grant T15LM011271 (to M.D.); National Science Foundation Graduate Fellowship 2015205295 (to R.M.P.); a Canadian Institute for Advanced Research fellowship (to H.C.); Japan Society
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/10/16
Y1 - 2018/10/16
N2 - Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.
AB - Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.
KW - Cancer mutational landscapes
KW - Comparative genomics
KW - Hepatocellular carcinoma
KW - Immune analysis
KW - Mouse models
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U2 - 10.1073/pnas.1811029115
DO - 10.1073/pnas.1811029115
M3 - Article
C2 - 30287485
AN - SCOPUS:85055001425
SN - 0027-8424
VL - 115
SP - E9879-E9888
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -