The Cancer Genome Atlas (TCGA) has compiled genomic, epigenomic, and proteomic data from more than 10,000 samples derived from 33 types of cancer, aiming to improve our understanding of the molecular ...basis of cancer development. Availability of these genome-wide information provides an unprecedented opportunity for uncovering new key regulators of signaling pathways or new roles of pre-existing members in pathways. To take advantage of the advancement, it will be necessary to learn systematic approaches that can help to uncover novel genes reflecting genetic alterations, prognosis, or response to treatments. This minireview describes the updated status of TCGA project and explains how to use TCGA data. BMB Reports 2016; 49(11): 607-611.
The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current ...advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC.
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for ...patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, ...progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A‐HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC‐prone microenvironment. Here, we have identified and validated an A‐HSC‐specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue‐related, A‐HSC‐specific gene expression is associated with recurrence and poor survival. Analyses of A‐HSC‐specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A‐HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A‐HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. Conclusion: A‐HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse. (Hepatology 2015;62:481–495
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.
Gene expression data from a TCGA cohort (
= 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 (
= 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.
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 (
= 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor HR, 1.5; 95% confidence interval (CI), 1.2-1.9;
= 0.001. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16-0.94;
= 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36-1.89;
= 0.65).
Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted.
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial ...phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.
In the adult liver, the Hippo pathway mammalian STE20‐like protein kinases 1 and 2 and large tumor suppressor homologs 1 and 2 (LATS1/2) control activation of the transcriptional coactivators ...Yes‐associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ) in hepatocytes and biliary epithelial cells, thereby regulating liver cell proliferation, differentiation, and malignant transformation. Less is known about the contribution of Hippo signaling to liver development. We used conditional mutagenesis to show that the Hippo signaling pathway kinases LATS1 and LATS2 are redundantly required during mouse liver development to repress YAP and TAZ in both the biliary epithelial and hepatocyte lineages. In the absence of LATS1/2, biliary epithelial cells exhibit excess proliferation while hepatoblasts fail to mature into hepatocytes, defects that result in perinatal lethality. Using an in vitro hepatocyte differentiation assay, we demonstrate that YAP activity decreases and Hippo pathway kinase activities increase upon differentiation. In addition, we show that YAP activation in vitro, resulting from either depletion of its negative regulators LATS1/2 or expression of a mutant form of YAP that is less efficiently phosphorylated by LATS1/2, results in transcriptional suppression of genes that normally accompany hepatocyte maturation. Moreover, we provide evidence that YAP activity is repressed by Hippo pathway activation upon hepatocytic maturation in vitro. Finally, we examine the localization of YAP during fetal liver development and show that higher levels of YAP are found in biliary epithelial cells, while in hepatocytes YAP levels decrease with hepatocyte maturation. Conclusion: Hippo signaling, mediated by the LATS1 and LATS2 kinases, is required to restrict YAP and TAZ activation during both biliary and hepatocyte differentiation. These findings suggest that dynamic regulation of the Hippo signaling pathway plays an important role in differentiation and functional maturation of the liver. (Hepatology 2016;64:1757‐1772).
Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, ...which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation.
How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ ...size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1, mst1, and mst2, orthologs of Drosophila Salvador and hippo, respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5-6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1, a second core Hippo signaling component that facilitates activation of mst1 and mst2. Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.
The interaction between RNA‐binding proteins (RBPs) and RNA plays an important role in regulating cellular function. However, decoding genome‐wide protein–RNA regulatory networks as well as how ...cancer‐related mutations impair RNA regulatory activities in hepatocellular carcinoma (HCC) remains mostly undetermined. We explored the genetic alteration patterns of RBPs and found that deleterious mutations are likely to occur on the surface of RBPs. We then constructed protein–RNA interactome networks by integration of target binding screens and expression profiles. Network analysis highlights regulatory principles among interacting RBPs. In addition, somatic mutations selectively target functionally important genes (cancer genes, core fitness genes, or conserved genes) and perturb the RBP–gene regulatory networks in cancer. These regulatory patterns were further validated using independent data. A computational method (Mutational Effect on RNA Interactome Topology) and a web‐based, user‐friendly resource were further proposed to analyze the RBP–gene regulatory networks across cancer types. Pan‐cancer analysis also suggests that cancer cells selectively target “vulnerability” genes to perturb protein–RNA interactome that is involved in cancer hallmark–related functions. Specifically, we experimentally validated four pairs of RBP–gene interactions perturbed by mutations in HCC, which play critical roles in cell proliferation. Based on the expression of perturbed RBP and target genes, we identified three subtypes of HCC with different survival rates. Conclusion: Our results provide a valuable resource for characterizing somatic mutation‐perturbed protein–RNA regulatory networks in HCC, yielding valuable insights into the genotype–phenotype relationships underlying human cancer, and potential biomarkers for precision medicine.
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