Background-It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue.

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomics-based classification for HCC have yielded highly divergent results, indicating difficulty to identify unified molecular anatomy. We performed a meta-analysis of gene expression profiles in datasets from 8 independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed 3 robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation, but rather was the result of TGF-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene-expression profiles, and highlight the power of integrating of multiple datasets to define a robust molecular taxonomy of the disease.

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs5–8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis.

Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection.

BACKGROUND-The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. Based on its role in cell growth and differentiation, we evaluated mTOR signaling activation in human HCC, as well as the anti-tumoral effect of a dual-level blockade of the mTOR pathway.

Objective Colorectal cancer is typically classified into proximal colon, distal colon, and rectal cancer. Tumor genetic and epigenetic features differ by tumor location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, we hypothesized that tumor molecular features might gradually change along bowel subsites, rather than abruptly change at splenic flexure. Design Utilizing 1443 colorectal cancers in two U.S. nationwide prospective cohort studies, we examined the frequencies of molecular features [CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation, and BRAF, KRAS, and PIK3CA mutations] along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum). Linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis. Results The frequencies of CIMP-high, MSI-high, and BRAF mutation gradually increased from rectum (<2.3%) to ascending colon (36–40%), followed by falls in the cecum (12–22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence for non-linearity (p>0.09). Cecal cancers exhibited the highest frequency of KRAS mutations (52% vs. 27–35% in other sites; p<0.0001). Conclusions The frequencies of CIMP-high, MSI-high, and BRAF mutation in cancer increased gradually along colorectum subsites from rectum to ascending colon. Our novel data challenge the common conception of discrete molecular features of proximal vs. distal colorectal cancers, and have substantial impact on clinical, translational, and epidemiology research, which has typically been performed with dichotomous classification of proximal vs. distal tumors.