Project description:Genome-wide DNA copy number profiles of multiple hepatocellular carcinoma tumors and non-tumor liver tissues from the same patients. Introduction: Hepatocellular Carcinoma (HCC) is the second cause of cancer-related death worldwide. Understanding tumor heterogeneity is relevant for the pathogenesis and treatment of this neoplasm. Particularly, whether multinodular tumors result from intrahepatic metastasis (IM or clonal tumors) or de novo cancers (synchronic tumors) have direct implications in treatment decisionmaking for resection and transplantation. We aimed to assess the genomic heterogeneity of multifocal HCC using single-nucleotide polymorphism (SNP) and gene expression analyses. Methods: Among 544 HCC patients consecutively transplanted at Mount Sinai Hospital between 1990- 2007, we selected 18 patients with a total of 42 multinodular tumors (2-3 non-satellite foci HCCs) for this molecular study. Formalin-fixed blocks were collected for each tumor along with corresponding clinico-pathological data. SNP array and gene expression profiling was generated. Clonality was defined by measuring the similarity of genome-wide copy number variation (CNV) profiles between two nodules. Unsupervised hierarchical clustering based on gene expression data was performed to measure genetic proximity between each tumor. Prediction of previously published signatures was performed using Nearest Template Prediction (NTP). Association of clonality with clinic-pathological parameters was assessed. Results: A total of 42 tumors have been analyzed (10 patients- 2 tumors; 8- 3 tumors). Most patients were male (17/18, 95%) with median age of 53-yr-old (range 39–67), HCV (10/18, 56%) or HBV infection (6/18, 33%). Median tumor size was 3 cm (range 1.5-6.5), satellites were present in 3 (17%) and vascular invasion in 11 patients (61%), respectively. CNV profiles predicted clonal tumors in 38% (6/16) and non-clonality in 62% of cases (10/16). CNV profiles of the remaining 2 cases were not informative. Clonal tumors were significantly associated with HCV infected patients (5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were synchronic tumors (0/6 vs 6/10, p=0.03). Furthermore, clonal tumors were significantly associated with presence of satellites and shorter time-torecurrence. Assessment of genetic proximity based on gene expression revealed that each clonal tumor showed proximity to its paired tumor and clustered around the same node (6/6,100%) as opposed to non-clonal (2/9,22%). When exploring molecular subclasses within clonal tumors (intrahepatic metastases), while half of them retained the molecular fingerprint, the other half switch to more aggressive subclasses. Conversely, all non-clonal tumors within the same patient belonged to distinct molecular subclasses. Conclusion: Multinodular HCCs undergoing transplantation are molecularly heterogeneous. Using CNV profiling we identified clonal multinodular tumors (true intrahepatic metastasis) in 40% of cases and de novo tumors in 60%. Clonal tumors were significantly associated with HCV infection, satellites and recurrence. Genetic proximity was observed in clonal tumors, but molecular subclasses prediction revealed that intrahepatic metastases share more aggressive subclasses in half of cases.

Project description:Genome-wide gene expression profiles of multiple hepatocellular carcinoma tumors and non-tumor liver tissues from the same patients. Introduction: Hepatocellular Carcinoma (HCC) is the second cause of cancer-related death worldwide. Understanding tumor heterogeneity is relevant for the pathogenesis and treatment of this neoplasm. Particularly, whether multinodular tumors result from intrahepatic metastasis (IM or clonal tumors) or de novo cancers (synchronic tumors) have direct implications in treatment decisionmaking for resection and transplantation. We aimed to assess the genomic heterogeneity of multifocal HCC using single-nucleotide polymorphism (SNP) and gene expression analyses. Methods: Among 544 HCC patients consecutively transplanted at Mount Sinai Hospital between 1990- 2007, we selected 18 patients with a total of 42 multinodular tumors (2-3 non-satellite foci HCCs) for this molecular study. Formalin-fixed blocks were collected for each tumor along with corresponding clinico-pathological data. SNP array and gene expression profiling was generated. Clonality was defined by measuring the similarity of genome-wide copy number variation (CNV) profiles between two nodules. Unsupervised hierarchical clustering based on gene expression data was performed to measure genetic proximity between each tumor. Prediction of previously published signatures was performed using Nearest Template Prediction (NTP). Association of clonality with clinic-pathological parameters was assessed. Results: A total of 42 tumors have been analyzed (10 patients- 2 tumors; 8- 3 tumors). Most patients were male (17/18, 95%) with median age of 53-yr-old (range 39–67), HCV (10/18, 56%) or HBV infection (6/18, 33%). Median tumor size was 3 cm (range 1.5-6.5), satellites were present in 3 (17%) and vascular invasion in 11 patients (61%), respectively. CNV profiles predicted clonal tumors in 38% (6/16) and non-clonality in 62% of cases (10/16). CNV profiles of the remaining 2 cases were not informative. Clonal tumors were significantly associated with HCV infected patients (5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were synchronic tumors (0/6 vs 6/10, p=0.03). Furthermore, clonal tumors were significantly associated with presence of satellites and shorter time-torecurrence. Assessment of genetic proximity based on gene expression revealed that each clonal tumor showed proximity to its paired tumor and clustered around the same node (6/6,100%) as opposed to non-clonal (2/9,22%). When exploring molecular subclasses within clonal tumors (intrahepatic metastases), while half of them retained the molecular fingerprint, the other half switch to more aggressive subclasses. Conversely, all non-clonal tumors within the same patient belonged to distinct molecular subclasses. Conclusion: Multinodular HCCs undergoing transplantation are molecularly heterogeneous. Using CNV profiling we identified clonal multinodular tumors (true intrahepatic metastasis) in 40% of cases and de novo tumors in 60%. Clonal tumors were significantly associated with HCV infection, satellites and recurrence. Genetic proximity was observed in clonal tumors, but molecular subclasses prediction revealed that intrahepatic metastases share more aggressive subclasses in half of cases.

Project description:Chromosomal DNA copy number alterations are a hallmark of human malignancies, including hepatocellular carcinoma (HCC). However, which oncogenes or tumor suppressors located on regions with DNA copy number aberration may contribute to HCC initiation and progression still remain obscure. Here we performed a genome-wide DNA copy number analysis on human HCC samples to identify novel potential oncogenes or tumor suppressors with DNA copy number aberrations. Genome-wide DNA copy numbers analysis was performed with single nucleotide polymorphism micoarray. RT-PCR and immunohistochemical staining were employed to evaluate the NOXIN expression in HCC samples. Colony formation, cell cycle analysis and tumor xenograft assays were performed to assess the role of NOXIN in HCC cells. Reciprocal co-immunoprecipitation experiments were used to detect the interaction between NOXIN and DNA polymerase a primase. Genome-wide DNA copy number analysis on 43 paired HCC samples indentified the smallest DNA amplification region containing NOXIN, along with the elevated transcript. NOXIN overexpression was significantly associated with HCC tumor stage. Enforced NOXIN promoted cellular proliferation, colony formation, cell migration and in vivo tumorigenicity, whereas RNA interference against NOXIN can attenuate these effects. Interestingly, NOXIN overexpression can accelerate the G1-S transition of cell cycle progression through enhancing DNA synthesis in HCC cells, as indicated by bromodeoxyuridine incorporation. Furthermore, NOXIN can interact with DNA polymerase a, implying that NOXIN may promote de novo DNA synthesis via affiliating formation of DNA polymerase-primase complex. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from hepatocellular carcinoma and adjacent liver tissue samples. Copy number analysis of Affymetrix 500K SNP arrays was performed for 43 hepatocellular carcinoma tissue samples, which their adjacent liver tissues were used as references for copy number inference.

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