Copy number aberrations （CNAs） in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma （HCC）. This study wa...Copy number aberrations （CNAs） in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma （HCC）. This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months （range, 2.6-108.6 months）. One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 （33.3%） of the 66 HCC cases. The most recurrent gains （with frequencies 〉20%） were 8q 13.3-21.3, 8q21.3-23.3, 8q23.3-24.13, 8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival （P=0.010）. Multivariate Cox analysis identified 8q24.13- 24.3 gain as an independent prognostic factor for poor overall survival （HR=2.47; 95% CI=1.16-5.26; P=0.019）. A panel of 17 genes within the 8q24.13-24.3 region, including ATAD2, SQLE, PVT1, ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2, SQLE, PVT1, ASAP1, and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.展开更多
AIM To identify chromosomal copy number aberrations(CNAs) in early-stage hepatocellular carcinoma(HCC) and analyze whether they are correlated with patient prognosis.METHODS One hundred and twenty patients with early-...AIM To identify chromosomal copy number aberrations(CNAs) in early-stage hepatocellular carcinoma(HCC) and analyze whether they are correlated with patient prognosis.METHODS One hundred and twenty patients with early-stage HCC were enrolled in our study, with the collection of formalin fixed, paraffin-embedded(FFPE) specimens and clinicopathological data. Tumor areas were marked by certified pathologists on a hematoxylin and eosinstained slide, and cancer and adjacent non-cancerous tissues underwent extraction of DNA, which was analyzed with the Affymetrix Onco Scan platform to assess CNAs and loss of heterozygosity(LOH). Ten individuals with nonmalignant disease were used as the control group. Another cohort consisting of 40 patients with stage Ⅰ/Ⅱ HCC were enrolled to analyze gene expression and to correlate findings with the Onco Scan data.RESULTS Copy number amplifications occurred at chromosomes 1 q21.1-q44 and 8 q12.3-24.3 and deletions were found at 4 q13.1-q35.2, 8 p 23.2-21.1, 16 q23.3-24.3, and 17 p13.3-12, while LOH commonly occurred at 1 p32.3, 3 p21.31, 8 p23.2-21.1, 16 q22.1-24.3, and 17 p 13.3-11 in early-stage HCC. Using Cox regression analysis, we also found that a higher percentage of genome change(≥ 60%) was an independent factor for worse prognosis in early-stage HCC(P = 0.031). Among the 875 genes in the Onco Scan Gene Chip, six were independent predictors of worse disease-free survival, of which three were amplified(MYC, ELAC2, and SYK) and three were deleted(GAK, MECOM, and WRN). Further, patients with HCC who exhibited ≥ 3 CNAs involving these six genes have worse outcomes compared to those who had < 3 CNAs(P < 0.001). Similarly, Asian patients with stage I HCC from The Cancer Genome Atlas harboring CNAs with these genes were also predicted to have poorer outcomes.CONCLUSION Patients with early-stage HCC and increased genome change or CNAs involving MYC, ELAC2, SYK, GAK, MECOM, or WRN are at risk for poorer outcome after resection.展开更多
Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma(HCC),however,reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are...Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma(HCC),however,reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking.This study was to identify gene-level copy number aberrations(CNAs)related to extrahepatic metastasis-free survival of HCC patients,and further examine the associations between CNAs and gene expression.Array comparative genomic hybridization(aCGH)and expression array were used to analyze gene CNAs and expression levels,respectively.The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months.The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC.We observed that gains at MDM4 and BCL2L1,and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients.Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain,while APC and FBXW7 were significantly downregulated in HCCs with gene loss.We concluded that gene gains at MDM4 and BCL2L1,and losses at APC and FBXW7,with concordant expression changes,were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.展开更多
BACKGROUND Lymphovascular invasion (LVI) is suggested to be an early and important step in tumor progression toward metastasis, but its prognostic value and genetic mechanisms in colorectal cancer (CRC) have not been ...BACKGROUND Lymphovascular invasion (LVI) is suggested to be an early and important step in tumor progression toward metastasis, but its prognostic value and genetic mechanisms in colorectal cancer (CRC) have not been well investigated. AIM To investigate the prognostic value of LVI in CRC and identify the associated genomic alterations. METHODS We performed a retrospective analysis of 1219 CRC patients and evaluated the prognostic value of LVI for overall survival by the Kaplan-Meier method and multivariate Cox regression analysis. We also performed an array-based comparative genomic hybridization analysis of 47 fresh CRC samples to examine the genomic alterations associated with LVI. A decision tree model was applied to identify special DNA copy number alterations (DCNAs) for differentiating between CRCs with and without LVI. Functional enrichment and protein-protein interaction network analyses were conducted to explore the potential molecular mechanisms of LVI. RESULTS LVI was detected in 150 (12.3%) of 1219 CRCs, and the presence was positively associated with higher histological grade and advanced tumor stage (both P < 0.001). Compared with the non-LVI group, the LVI group showed a 1.77-fold (95% confidence interval: 1.40-2.25, P < 0.001) increased risk of death and a significantly lower 5-year overall survival rate (P < 0.001). Based on the comparative genomic hybridization data, 184 DCNAs (105 gains and 79 losses) were identified to be significantly related to LVI (P < 0.05), and the majority were located at 22q, 17q, 10q, and 6q. We further constructed a decision tree classifier including seven special DCNAs, which could distinguish CRCs with LVI from those without it at an accuracy of 95.7%. Functional enrichment and proteinprotein interaction network analyses revealed that the genomic alterations related to LVI were correlated with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling. CONCLUSION LVI is an independent predictor for survival in CRC, and its development may 展开更多
基金This project was supported by grants from the Medical Science and Technology Innovation Fund ofPLA, Nanjing branch, China （No. 14ZD07 08MA023） and Ningbo Nature Science Foundation Program （No. 2009A610126）.
文摘Copy number aberrations （CNAs） in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma （HCC）. This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months （range, 2.6-108.6 months）. One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 （33.3%） of the 66 HCC cases. The most recurrent gains （with frequencies 〉20%） were 8q 13.3-21.3, 8q21.3-23.3, 8q23.3-24.13, 8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival （P=0.010）. Multivariate Cox analysis identified 8q24.13- 24.3 gain as an independent prognostic factor for poor overall survival （HR=2.47; 95% CI=1.16-5.26; P=0.019）. A panel of 17 genes within the 8q24.13-24.3 region, including ATAD2, SQLE, PVT1, ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2, SQLE, PVT1, ASAP1, and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.
基金Supported by the Chang Gung Memorial Hospital in Taiwan,No.CMRPG 3C0951-3 and No.CMRPG 3A0671 to Yu MC,and No.CMRPD3F0011 to Tsai CN
文摘AIM To identify chromosomal copy number aberrations(CNAs) in early-stage hepatocellular carcinoma(HCC) and analyze whether they are correlated with patient prognosis.METHODS One hundred and twenty patients with early-stage HCC were enrolled in our study, with the collection of formalin fixed, paraffin-embedded(FFPE) specimens and clinicopathological data. Tumor areas were marked by certified pathologists on a hematoxylin and eosinstained slide, and cancer and adjacent non-cancerous tissues underwent extraction of DNA, which was analyzed with the Affymetrix Onco Scan platform to assess CNAs and loss of heterozygosity(LOH). Ten individuals with nonmalignant disease were used as the control group. Another cohort consisting of 40 patients with stage Ⅰ/Ⅱ HCC were enrolled to analyze gene expression and to correlate findings with the Onco Scan data.RESULTS Copy number amplifications occurred at chromosomes 1 q21.1-q44 and 8 q12.3-24.3 and deletions were found at 4 q13.1-q35.2, 8 p 23.2-21.1, 16 q23.3-24.3, and 17 p13.3-12, while LOH commonly occurred at 1 p32.3, 3 p21.31, 8 p23.2-21.1, 16 q22.1-24.3, and 17 p 13.3-11 in early-stage HCC. Using Cox regression analysis, we also found that a higher percentage of genome change(≥ 60%) was an independent factor for worse prognosis in early-stage HCC(P = 0.031). Among the 875 genes in the Onco Scan Gene Chip, six were independent predictors of worse disease-free survival, of which three were amplified(MYC, ELAC2, and SYK) and three were deleted(GAK, MECOM, and WRN). Further, patients with HCC who exhibited ≥ 3 CNAs involving these six genes have worse outcomes compared to those who had < 3 CNAs(P < 0.001). Similarly, Asian patients with stage I HCC from The Cancer Genome Atlas harboring CNAs with these genes were also predicted to have poorer outcomes.CONCLUSION Patients with early-stage HCC and increased genome change or CNAs involving MYC, ELAC2, SYK, GAK, MECOM, or WRN are at risk for poorer outcome after resection.
基金This work was supported by grants from the Medical Science and Technology Innovation Fund of PLA,Nanjing branch,China(No.14ZD07 and No.08MA023)Ningbo Natural Science Foundation Program(No.2009A610126).
文摘Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma(HCC),however,reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking.This study was to identify gene-level copy number aberrations(CNAs)related to extrahepatic metastasis-free survival of HCC patients,and further examine the associations between CNAs and gene expression.Array comparative genomic hybridization(aCGH)and expression array were used to analyze gene CNAs and expression levels,respectively.The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months.The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC.We observed that gains at MDM4 and BCL2L1,and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients.Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain,while APC and FBXW7 were significantly downregulated in HCCs with gene loss.We concluded that gene gains at MDM4 and BCL2L1,and losses at APC and FBXW7,with concordant expression changes,were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.
基金the National Natural Science Foundation of China,No.81874201Shanghai Municipal Commission of Health and Family Planning,No.ZK2015A32 and No.201840359
文摘BACKGROUND Lymphovascular invasion (LVI) is suggested to be an early and important step in tumor progression toward metastasis, but its prognostic value and genetic mechanisms in colorectal cancer (CRC) have not been well investigated. AIM To investigate the prognostic value of LVI in CRC and identify the associated genomic alterations. METHODS We performed a retrospective analysis of 1219 CRC patients and evaluated the prognostic value of LVI for overall survival by the Kaplan-Meier method and multivariate Cox regression analysis. We also performed an array-based comparative genomic hybridization analysis of 47 fresh CRC samples to examine the genomic alterations associated with LVI. A decision tree model was applied to identify special DNA copy number alterations (DCNAs) for differentiating between CRCs with and without LVI. Functional enrichment and protein-protein interaction network analyses were conducted to explore the potential molecular mechanisms of LVI. RESULTS LVI was detected in 150 (12.3%) of 1219 CRCs, and the presence was positively associated with higher histological grade and advanced tumor stage (both P < 0.001). Compared with the non-LVI group, the LVI group showed a 1.77-fold (95% confidence interval: 1.40-2.25, P < 0.001) increased risk of death and a significantly lower 5-year overall survival rate (P < 0.001). Based on the comparative genomic hybridization data, 184 DCNAs (105 gains and 79 losses) were identified to be significantly related to LVI (P < 0.05), and the majority were located at 22q, 17q, 10q, and 6q. We further constructed a decision tree classifier including seven special DCNAs, which could distinguish CRCs with LVI from those without it at an accuracy of 95.7%. Functional enrichment and proteinprotein interaction network analyses revealed that the genomic alterations related to LVI were correlated with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling. CONCLUSION LVI is an independent predictor for survival in CRC, and its development may
