[9-14] This

scarcity of kinase mutations suggests that HCC might be rarely susceptible to the dramatic responses to kinase inhibitors that are observed in other cancer types.[34, 35] In contrast, the frequent mutation of MLL histone methyltransferases—as well as ARID ATP-dependent nucleosome remodeling enzymes identified in previous studies—suggests that epigenetic regulatory enzymes may represent important target genes in HCC. Because most studies to date have been conducted on surgically resected tumors, we have little knowledge about the genetic Panobinostat cost alterations that occur in either very early lesions treated with ablative modalities as well as later stages of HCC progression that are not amenable to surgical treatment. Our understanding of tumor evolution could be improved by more-sensitive technologies that could sequence gDNA selleck kinase inhibitor from core biopsy specimens. Another confounding issue with genomic profiling is the high rate of intratumor heterogeneity. Indeed,

a pioneering study demonstrated considerable clonal heterogeneity within a single tumor lesion, with allelic frequencies as low as 13%.[10] In this series, we present the whole-exome sequencing analysis of a large diverse series of HCC tumors and matching normal liver tissue. Our results support the genetic heterogeneity of HCC in that most genes were mutated in few (<20%) of the samples analyzed; however, analysis of gene families have indicated potentially important pathways, including MLL and NFE2L2-KEAP1, that are altered in subsets of tumors. Overexpression of several genes of interest were observed in tumors with identified mutations, but also in adjacent nontumor liver samples, which suggests a role of these genes in the premalignant “field effect” selleck chemicals llc that is observed in the unaffected liver of HCC patients.[36] We observed phenotypic differences in HCC according to gene

mutation status, including p53 mutation status as an independent predictor of recurrence-free survival. Several other genes of interest demonstrated trends in time and risk of recurrence; these observations were limited by sample size and require further investigation in larger studies. The lack of correlation between traditional prognostic features, such as tumor size, number, and vascular invasion, indicates that mutational profiling may enhance our ability to develop more-predictive models of tumor behavior. Further investigation is required to enhance our understanding of the full breadth of gene mutations in HCC and identify clinically relevant genes and pathways that can enhance our understanding of hepatocarcinogenesis and develop individualized therapy based on HCC genetic signatures. The authors thank Bert O’Neil for a critical revision of this manuscript. Additional Supporting Information may be found in the online version of this article. “
“We estimated the global burden of hepatitis E virus (HEV) genotypes 1 and 2 in 2005.