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Project description:Hepatocellular carcinoma (HCC) is the predominant primary liver cancer and an increasing cause of cancer-related deaths worldwide, due in part through increased obesity-associated nonalcoholic steatohepatitis (NASH) and associated fibrosis. The Notch signaling pathway is inappropriately “reactivated” in hepatocytes in obesity and plays an active role in the pathogenesis of NASH-associated fibrosis. We aimed to understand the involvement of Notch in the pathogenesis of mouse and human HCC.
2020-09-28 | GSE154550 | GEO
Project description:Hepatocellular carcinoma (HCC) is the predominant primary liver cancer and an increasing cause of cancer-related deaths worldwide, due in part through increased obesity-associated nonalcoholic steatohepatitis (NASH) and associated fibrosis. The Notch signaling pathway is inappropriately “reactivated” in hepatocytes in obesity and plays an active role in the pathogenesis of NASH-associated fibrosis. We aimed to understand the involvement of Notch in the pathogenesis of mouse and human HCC.
2020-09-28 | GSE154551 | GEO
Project description:Background & aimsThe hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC.MethodsUsing a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis.ResultsNotch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (β-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed β-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce β-catenin-inactive HCC in mice with NASH. Notch and β-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to β-catenin-dependent tumor development.ConclusionsNotch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations.Lay summaryThe Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.
| S-EPMC7897246 | biostudies-literature
Project description:Notch activity determines a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features
| PRJNA646654 | ENA
Project description:Notch activity determines a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features [Venus]
| PRJNA646661 | ENA
Project description:Notch activity determines a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features [L-NICD]
| PRJNA646662 | ENA
Project description:Hepatocellular carcinoma (HCC) is one of the most common malignancies and displays high heterogeneity of molecular phenotypes. We investigated DNA damage repair (DDR) alterations in HCC by integrating multi-omics data. HCC patients were classified into two heterogeneous subtypes with distinct clinical and molecular features: the DDR-activated subtype and the DDR-suppressed subtype. The DDR-activated subgroup is characterized by inferior prognosis and clinicopathological features that result in aggressive clinical behavior. Tumors of the DDR-suppressed class, which have distinct clinical and molecular characteristics, tend to have superior survival. A DDR subtype signature was ultimately generated to enable HCC DDR classification, and the results were confirmed by using multi-layer date cohorts. Furthermore, immune profiles and immunotherapy responses are also different between the two DDR subtypes. Altogether, this study illustrates the DDR heterogeneity of HCCs and is helpful to the understanding of personalized clinicopathological and molecular mechanisms responsible for unique tumor DDR profiles.
| S-EPMC8387599 | biostudies-literature
Project description:We have previously characterized a tumor stroma expression signature in a subset of breast tumors that correlates with better clinical outcome. The purpose of this study is to determine whether this stromal signature, termed the "DTF fibroblast" (desmoid-type fibromatosis) signature, is specific to breast cancer or is a common stromal response found in different types of cancer.The DTF fibroblast signature was applied to gene expression profiles from five ovarian, five lung, two colon, and three prostate cancer expression microarray datasets. In addition, two different tissue microarrays of 204 ovarian tumors and 140 colon tumors were examined for the expression of previously characterized protein markers of DTF fibroblast signature. The DTF fibroblast stromal response was then correlated with clinicopathologic features.The DTF fibroblast signature is robustly present in ovarian, lung, and colon carcinomas. Both expression microarray data and immunohistochemistry show that the subset of ovarian tumors with strong DTF fibroblast signature expression has statistically significant, worse survival outcomes. No reproducible survival differences were found in either the lung or the colon cancers. The prostate cancers failed to show a DTF fibroblast signature. Multivariant analysis showed that DTF fibroblast signature was significantly more prognostic than the proliferation status in ovarian carcinomas.Our results suggest that the DTF fibroblast signature is a common tumor stroma signature in different types of cancer, including ovarian, lung, and colon carcinomas. Our findings provide further insight into the DTF fibroblast stromal responses across different types of carcinomas and their potential as prognostic and therapeutic targets.
| S-EPMC3778157 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in Taiwan. CD44, one of the well-known tumor markers, plays an essential role in tumor cell differentiation, invasion, and metastasis. We investigated the CD44 single-nucleotide polymorphisms (SNPs) with environmental risk factors related to HCC susceptibility and clinicopathological characteristics. Six SNPs of CD44 were analyzed using a real-time polymerase chain reaction (PCR) in 203 patients with HCC and in 561 cancer-free controls. We determined that the individuals carrying at least one G allele at CD44 rs187115 has higher risk of developing HCC than did wild-type (AA) carriers. We further observed that the CD44 rs187115 polymorphisms with at least one G allele had a higher frequency of distribution in nonsmoking stage III/IV HCC patients, compared with wild-type carriers. Our results suggested that patients with CD44 rs187115 variant genotypes (AG+GG) were associated with a higher risk of HCC development and that these patients might possess chemoresistance, causing more likely progression to late-stage HCC than wild-type carriers without the overexpression of CD44 induced by heavy smoking. CD44 rs187115 might be involved in CD44 isoform expression of p53 stress response in HCC and provide a marker for predicting worst-case prognosis of HCC.
| S-EPMC4058263 | biostudies-literature
Project description:PurposeThe anaplastic large cell kinase gene (ALK) is rearranged in approximately 5% of lung adenocarcinomas within the Asian population. We evaluated the incidence and the characteristics of ALK-rearranged lung adenocarcinomas within the western population and the optimal diagnostic modality to detect ALK rearrangements in routine clinical practice.Experimental designWe tested 358 lung adenocarcinomas from three institutions for ALK rearrangements by fluorescent in situ hybridization (FISH) and immunohistochemistry with and without tyramide amplification. The clinicopathologic characteristics of tumors with and without ALK rearrangements were compared.ResultsWe identified 20 (5.6%) lung adenocarcinomas with ALK rearrangements within our cohort of western patients. ALK rearrangement was associated with younger age (P = 0.0002), never smoking (P < 0.0001), advanced clinical stage (P = 0.0001), and a solid histology with signet-ring cells (P < 0.0001). ALK rearrangement was identified by FISH in 95% of cases and immunohistochemistry with and without tyramide amplification in 80% and 40% of cases, respectively, but neither FISH nor immunohistochemistry alone detected all cases with ALK rearrangement on initial screening. None of the ALK-rearranged tumors harbored coexisting EGFR mutations.ConclusionsLung adenocarcinomas with ALK rearrangements are uncommon in the western population and represent a distinct entity of carcinomas with unique characteristics. For suspected cases, dual diagnostic testing, with FISH and immunohistochemistry, should be considered to accurately identify lung adenocarcinomas with ALK rearrangement.
| S-EPMC2865649 | biostudies-literature