Article first published online: 19 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 120–130, January 2013
How to Cite
Keng, V. W., Sia, D., Sarver, A. L., Tschida, B. R., Fan, D., Alsinet, C., Solé, M., Lee, W. L., Kuka, T. P., Moriarity, B. S., Villanueva, A., Dupuy, A. J., Riordan, J. D., Bell, J. B., T.Silverstein, K. A., Llovet, J. M. and Largaespada, D. A. (2013), Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. Hepatology, 57: 120–130. doi: 10.1002/hep.26004
Potential conflict of interest: Dr. Llovet consults for and received grants from Bayer and Bristol-Myers Squibb. He also consults for ImClone and Biocompatibles.
J. M. L. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), the European Comission-FP7 Framework (HEPTROMIC, Proposal No. 259744), The Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2010-16055), and the Asociación Española Contra el Cáncer. D. A. L. is supported by grants U01 CA84221 and R01 CA113636 from the National Cancer Institute.
- Issue published online: 7 JAN 2013
- Article first published online: 19 OCT 2012
- Accepted manuscript online: 16 AUG 2012 03:54AM EST
- Manuscript Accepted: 8 JUL 2012
- Manuscript Received: 19 MAR 2012
Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female mice (2/9, 22%). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression–based Poly7 subclass patients were predominantly male (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P < 0.001). Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC. (HEPATOLOGY 2013)