SUMMARY Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

In areas with a low prevalence of MDR bacteria.

Purpose The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Experimental Design Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. Results EBV subtype was associated with the best prognosis and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor (hazard ratio [HR] = 1.5; 95% confidence interval [CI] = 1.2–1.9; P = 0.001). Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR = 0.39; 95% CI = 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR = 0.83; 95% CI = 0.36–1.89; P = 0.65). Conclusion Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted.

Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.

The global burden of hepatitis B virus (HBV) infection is profound, and represents a public health threat as chronic infection can lead to liver cirrhosis, hepatocellular carcinoma, and death. The risk factors for chronic hepatitis B-related liver disease differ according to HBV endemicity, hepatitis B e-antigen seropositivity, and viral load. It is important to identify these risk factors and start antiviral treatment at an appropriate time according to current guidelines. The most crucial step in reducing HBV infection is prevention in infancy or early childhood, as infection at an early stage may lead to chronicity. South Korea was formerly an HBV-endemic area, but the epidemiology of HBV infection was changed by the introduction of vaccination in 1983 and nationwide immunization in 1995. The government and the private sector made efforts to reduce the prevalence of HBV infection, and Korea is on target to meet the World Health Organization goal of eliminating viral hepatitis by 2030. To eliminate hepatitis worldwide, the costs of antiviral treatment to prevent perinatal HBV transmission in pregnant women with high viremia should be covered by a national program, and strategies to reduce the prevalence of HBV infection in immigrant populations are needed.