Cancer incidence in Iran in 2014: Results of the Iranian National Population-based Cancer Registry

BackgroundWe aimed to report, for the first time, the results of the Iranian National Population-based Cancer Registry (INPCR) for the year 2014.MethodsTotal population of Iran in 2014 was 76,639,000. The INPCR covered 30 out of 31 provinces (98% of total population). It registered only cases diagnosed with malignant new primary tumors. The main sources for data collection included pathology center, hospitals as well as death registries. Quality assessment and analysis of data were performed by CanReg-5 software. Age standardized incidence rates (ASR) (per 100,000) were reported at national and subnational levels.ResultsOverall, 112,131 new cancer cases were registered in INPCR in 2014, of which 60,469 (53.9%) were male. The diagnosis of cancer was made by microscopic confirmation in 76,568 cases (68.28%). The ASRs of all cancers were 177.44 and 141.18 in male and female, respectively. Cancers of the stomach (ASR = 21.24), prostate (18.41) and colorectum (16.57) were the most common cancers in men and the top three cancers in women were malignancies of breast (34.53), colorectum (11.86) and stomach (9.44). The ASR of cervix uteri cancer in women was 1.78. Our findings suggested high incidence of cancers of the esophagus, stomach and lung in North/ North West of Iran.ConclusionOur results showed that Iran is a medium-risk area for incidence of cancers. We found differences in the most common cancers in Iran comparing to those reported for the World. Our results also suggested geographical diversities in incidence rates of cancers in different subdivisions of Iran.     

Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China

Our knowledge about molecular alterations during hepatocarcinogenesis is still fragmentary, due to lack of comprehensive genetic and epigenetic analyses in the same set of hepatocellular carcinomas (HCCs). In this study, we conducted a large-scale analysis, including mutation screening in 50 genes and methylation assays in three genes in 54 pairs of HCCs and their neighboring non-cancerous tissues. All samples were collected from the residents in Southeast China. We found HBV infection and chronic hepatitis/cirrhosis in 83.3% and 98.1% of the cases, respectively. Mutations were identified in 18 out of 54 (33.3%) samples, with p53 alterations in 14 cases and β-catenin mutations in four tumors. No mutations were identified in the neighboring tissues. Interestingly, 9 out of 14 (64.3%) tumors carrying p53 mutations displayed substitution of serine by arginine at codon 249, a characteristic change believed to be induced by aflatoxin-B1. Furthermore, p53 mutation was significantly associated with shorter recurrence-free survival (P = 0.004). The results also revealed aberrant methylation in two or more genes in as high as 90% of tumors and 40% of adjacent tissues. The frequency of RASSF1A hypermethylation was much higher than that of p16INK4a and HAI2 in both HCC and neighboring tissues, indicating that deregulation of RASSF1A may precede the other two genes. These data suggest that aberrant methylation occurs before mutation and is an early event in the development of this set of HCC. Our findings highlight p53 as a prognostic factor of HCC and RASSF1A as a potential target in preventing malignant transformation of hepatocytes.     

Influence of socioeconomic status on survival of hepatocellular carcinoma in the Ontario population; a population-based study, 1990-2009

Background

Research has shown that people from higher socioeconomic status (SES) have better hepatocellular carcinoma (HCC) survival outcomes, although no such research has been carried out in Canada. We aimed to assess if an association between SES and HCC survival existed in the Canadian context.

Methodology/Prinicpal Findings

We conducted a population-based cohort study linking HCC cases identified in the Ontario Cancer Registry between 1990 and 2009 to administrative and hospital data. Logistic regression and chi-squared tests were used to evaluate associations between SES (income quintile) and covariates. The Kaplan-Meier method was used to estimate survival. Sequential analysis of the proportional-hazards models were used to determine the association between SES and HCC survival controlling for potential prognostic covariates. During the period 1990–2009, 5,481 cases of HCC were identified. A significant association was found between SES and curative treatment (p = 0.0003), but no association was found between SES and non-curative treatment (p = 0.064), palliative treatment (p = 0.680), or ultrasound screening (p = 0.615). The median survival for the lowest SES was 8.5 months, compared to 8.8 months for the highest SES group. The age- and sex-adjusted proportional-hazards model showed statistically significant difference in HCC survival among the SES groups, with hazard ratio 0.905 (95% confidence intervals 0.821, 0.998) when comparing highest to lowest SES group. Further adjustments indicated that potentially curative treatment was the likely explanation for the association between SES and HCC survival.

Conclusions/Significance

Our findings suggest that a 10% HCC survival advantage exists for the higher SES groups. This association between SES and HCC survival is most likely a reflection of lack of access to care for low SES groups, revealing inequities in the Canadian healthcare system.     

Proteome analysis of hepatocellular carcinoma

Development of hepatocellular carcinoma (HCC) is a complex process involving multiple changes in gene expression and usually occurs in the presence of liver cirrhosis. In this research, we observed proteome alterations of three tissue types isolated from livers of HCC patients: normal, cirrhotic, and tumorous tissue. Proteome alterations were observed using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Comparing the tissue types with each other, a significant change in expression level was found in 21 proteins. Of these proteins, sarcosine dehydrogenase, liver carboxylesterase, peptidyl-prolyl isomerase A, and lamin B1 are considered novel HCC marker candidates. In particular, lamin B1 may be considered as a marker for cirrhosis, because its expression level changes considerably in cirrhotic tissue compared with normal tissue. The proteins revealed in this experiment can be used in the future for studies pertaining to hepatocarcinogenesis, or as diagnostic markers and therapeutic targets for HCC.     

Methylation-based molecular margin analysis in hepatocellular carcinoma

The positive surgical margins are associated with postsurgical recurrence in hepatocellular carcinoma patients, and molecular margin analysis is considered more sensitive in detecting preneoplastic lesions than conventional histological margin examination. To evaluate the feasibility of methylation-based molecular margin analysis in HCC and explore its clinical application, we investigated CDKN2A methylation status in the surgical margins of 20 HCC patients using a nested BS-MSP protocol and compared the methylation patterns in resection margins with those in the corresponding tumor and adjacent nonmalignant tissues. The results showed that a considerable frequency (35%, 7 of 20) of CDKN2A methylation was present in histologically negative margins, and methylation pattern analysis might be valuable for studying the cellular origin of recurrent carcinoma. Therefore, methylation-based molecular surgical margin analysis offers a promising tool in prognosis for HCC patients who underwent hepatectomy.     

Mortality burden and socioeconomic status in India

Background

The dimensions along which mortality is patterned in India remains unclear. We examined the specific contribution of social castes, household income, assets, and monthly per capita consumption to mortality differentials in India.

Methods and Findings

Cross-sectional data on 217 363 individuals from 41 554 households from the 2004–2005 India Human Development Survey was analyzed using multiple logistic regressions. Mortality differentials across social castes were attenuated after adjusting for household economic factors such as income and assets. Individuals living in the lowest income and assets quintiles had an increased risk of mortality with odds ratio (OR) of 1.66 (95% CI  = 1.23–2.24) in the bottom income quintile and OR of 2.94 (95% CI  = 1.66–5.22) in the bottom asset quintile. Counter-intuitively, individuals living in households with lowest monthly consumption per capita had significantly lower probability of death (OR  = 0.27, 95% CI  = 0.20–0.38).

Conclusions

Mortality burden in India is largely patterned on economic dimensions as opposed to caste dimensions, though caste may play an important role in predicting economic opportunities.     

Determination of HER-2/Neu status in hepatocellular carcinoma cases

Specific chromosome abnormalities and genetic changes in hepatocellular carcinoma (HCC) have been demonstrated by conventional cytogenetic studies or molecular cytogenetic approaches like comparative genomic hybridization and loss of heterozygosity analyses. HER-2/Neu amplification and expression has been studied as a molecular target for treatment of HCC, and there are conflicting results. We aimed to determine HER-2/Neu status in archive materials of HCC patients by fluorescence in situ hybridization (FISH). Among the 35 patients, 2 had HER-2/Neu amplification and 3 had increased chromosome 17 copy number. All these patients had grade 2 or 3 tumor with a diameter of 3-12 cm. We conclude that although HER-2/Neu amplification is not the primary mechanism in the development of liver tumors, it might play a role in one of the steps of multistage carcinogenesis.     

Neighborhood socioeconomic status and BMI differences by immigrant and legal status: Evidence from Utah

We build on recent work examining the BMI patterns of immigrants in the US by distinguishing between legal and undocumented immigrants. We find that undocumented women have relative odds of obesity that are about 10 percentage points higher than for legal immigrant women, and their relative odds of being overweight are about 40 percentage points higher. We also find that the odds of obesity and overweight status vary less across neighborhoods for undocumented women than for legal immigrant women. These patterns are not found among immigrant men: undocumented men have lower rates of obesity (by about 6 percentage points in terms of relative odds) and overweight (by about 12 percentage points) than do legal immigrant men, and there is little variation in the impact of neighborhood context across groups of men. We interpret these findings in terms of processes of acculturation among immigrant men and women.     

Selective isolation and analysis of glycoprotein fractions and their glycomes from hepatocellular carcinoma sera

As one of the most important post‐translational modifications, the discovery, isolation, and identification of glycoproteins are becoming increasingly important. In this study, a Con A‐magnetic particle conjugate‐based method was utilized to selectively isolate the glycoproteins and their glycomes from the healthy donor and hepatocellular carcinoma (HCC) case sera. The isolated glycoproteins and their N‐linked glycans were identified by LC‐ESI‐MS/MS and MALDI‐TOF/TOF‐MS, respectively. A total of 93 glycoproteins from the healthy donors and 85 glycoproteins from the HCC cases were identified. There were 34 different glycoproteins shown between the healthy donors (21/34) and the HCC cases (13/34). Twenty‐eight glycans from the healthy donors and 30 glycans from the HCC cases were detected and there were 22 different glycans shown between the healthy donors (10/22) and HCC cases (12/22). Among these glycoproteins, 50 were known to be N‐linked glycoproteins and three novel glycopeptides from two predicted potential glycoproteins were discovered. Moreover, lectin blotting, Western blotting and lectin/glyco‐antibody microarrays were applied to definitely elucidate the change of selective protein expressions and their glycosylation levels, the results indicated that the differences of the identified glycoproteins between the healthy donors and HCC cases were caused by the change of both protein expression and their glycosylation levels.     

Microarray-based gene expression analysis of hepatocellular carcinoma

Microarray studies have successfully shed light on various aspects of the molecular mechanisms behind the development of hepatocellular carcinoma (HCC), such as the identification of novel molecular subgroups and the genetic profiles associated with metastasis and venous invasion. These experiments, mainly comprising genome wide profiling, potentially represent the basis of novel targeted therapeutic strategies in HCC. In response, we summarize the multiple reported expression profiles in HCC associated with HCC development, novel subgroups, venous invasion and metastasis.     

Proteomic analysis of sera from hepatocellular carcinoma patients after radiofrequency ablation treatment

Comparative proteomic analysis was used to search for characteristic alterations in the sera of hepatocellular carcinoma (HCC) patients who had undergone curative radiofrequency ablation treatment. Serum samples collected from eight patients before and after treatment were subjected to 2-DE. Eighty-eight protein spots differentially expressed with the treatment were selected by clustering analysis, and the proteins were identified by MS based on MALDI-TOF/TOF analysis and public database searches. The statistical analysis suggested that four proteins decreased after treatment (pro-apolipoprotein, alpha2-HS glycoprotein, apolipoprotein A-IV precursor, and PRO1708/PRO2044, which is the carboxy terminal fragment of albumin) and that seven proteins were increased after treatment, including leucine-rich alpha2-glycoprotein and alpha1-antitrypsin. These data facilitate the identification of differentially expressed proteins that are involved in HCC carcinogenesis and provide candidate biomarkers for the development of diagnostic and therapeutic tools.     

Identification and analysis of immune-related subtypes of hepatocellular carcinoma

Hepatocellular carcinoma is a malignance that remains difficult to cure. Immunotherapy has shown its potential application in a variety of refractory malignancies. Due to the complexity of immune microenvironment of hepatocellular carcinoma, the efficacy of immunotherapy for hepatocellular carcinoma is not as effective as expected. Expression data of hepatocellular carcinoma from the TCGA and ICGC databases were used for classification and verification of hepatocellular carcinoma subtypes. The immune-related functions and pathways were identified via gene set enrichment analysis, while the sections denoting the subsets of the immune cells were estimated using the CIBERSORT algorithm. Immunity low (Immunity_L), immunity medium (Immunity_M), and immunity high (Immunity_H) were specified as the three immune-related subtypes of hepatocellular carcinoma. The quantity of stromal and immune cells was the most substantial in Immunity_H, compared to the other subtypes. Interestingly, the proportion of M0 macrophages decreased from Immunity_L to Immunity_H, while the proportion of CD8 T cells increased. Furthermore, the HLA genes expression levels, as well as those of six immune checkpoint genes were substantially lower in Immunity_L than in Immunity_H. Functional analysis was performed for 1512 differentially expressed genes between Immunity_L and Immunity_H. Finally, the PPI network was constructed with 118 nodes. The highest connectivity degree nodes were B2M, HLA-DRA, and HLA-DRB1. The above results were verified in ICGC-JP and ICGC-FR databases with a consistent trend. In this study, we divided hepatocellular carcinoma into three subtypes and explored the immune-related characteristics of these subtypes. These results may provide new insights for immunotherapy of hepatocellular carcinoma.     

Comparison of genome-scale DNA methylation profiles in hepatocellular carcinoma by viral status

Hepatocellular carcinoma (HCC) incidence has steadily increased in the US over the past 30 years. Our understanding of epigenetic regulation in HCC is still limited, especially the impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on aberrant DNA methylation. We performed genome-wide DNA methylation profiling in 33 fresh frozen tumor samples, including 10 HBV-HCC, 13 HCV-HCC, and 10 non-infected (NIV-HCC) using the Illumina HumanMethylation450 BeadChip. Gene expression profiling was also performed using the Illumina whole-genome DASL HT Assay. Biological influences and gene networks of the differentially-methylated (DM) CpG loci were predicted using the Ingenuity Pathway Analysis. Genome-wide methylation analysis identified 7, 26, and 98 DM loci between HBV-HCC vs. HCV-HCC, HBV-HCC vs. NIV-HCC, and HCV-HCC vs. NIV-HCC, respectively, at P < 5 × 10^?5 for each. Overall, the DM loci were highly enriched for enhancers (48%), promoters (37%), or CpG islands and surrounding regions (37%). Most DM loci were hypermethylated in HCV-HCC compared to HBV-HCC or NIV-HCC. The DM loci were associated with a variety of biological functions including Cell Morphology (HBV-HCC vs. NIV-HCC), Cell Death/ Survival (HBV-HCC vs. NIV-HCC), or Cellular Growth and Proliferation (HCV-HCC vs. NIV-HCC). A subset of the DM loci were correlated (either positively or negatively) with their gene expression or associated with alcohol consumption, BMI, cirrhosis, diabetes, and cigarette smoking. Our findings of differential methylation by viral infection lend insights into the potential effects of viral infection on the epigenetic regulation and further the development and progression of HCC.     

Proteomic analysis of autoantibodies in patients with hepatocellular carcinoma

To detect autoantibodies that could be diagnostic markers for hepatocellular carcinoma (HCC), we analyzed serum autoantibodies comprehensively that showed immunoreactivity to proteins in tumor tissue obtained from patients with HCC. Fifteen paired samples of HCC tissue and corresponding nontumorous liver tissue as well as five normal liver tissue samples were used in the study. A combination of proteomics and SEREX (serologic analysis of recombinant cDNA expression libraries) technique was used. Tissue proteins were separated by 2-DE, transferred onto PVDF membranes, and immunoblotted with autologous sera. By comparing each immunoblot pattern, we identified four immunoreactive spots with stronger staining intensity in tumorous tissues than in corresponding nontumorous tissues and in normal liver tissues. Matched proteins on 2-DE gels were identified by LC-MS/MS. These immunoreactive proteins were heat shock 70 kDa protein 1 (HSP70), glyceraldehyde 3-phosphate dehydrogenase, peroxiredoxin, and manganese superoxide dismutase (Mn-SOD). In HCC sera, occurrences of autoantibodies against these proteins were 7/15 (46.7%), 5/15 (33.3%), 5/15 (33.3%), and 6/15 (40.0%), respectively, whereas 2/20 (10.0%), 7/20 (35.0%), 0/20 (0.0%), and 2/20 (10.0%) were in control sera. Immunoblot analysis using commercially available purified proteins was performed to confirm the specificity of autoantibodies. By statistical analysis, autoantibodies against HSP70, peroxiredoxin, and Mn-SOD showed significantly high-frequency immunoreaction in HCC sera. The three antibodies were considered patient-specific antibodies in HCC and may be candidate diagnostic biomarkers for HCC.     

Polymorphism analyses of hepatitis B virus X gene in hepatocellular carcinoma patients from southern China

Chronic hepatitis B virus(HBV)infection is one of the major causes of hepatocellularcarcinoma(HCC),and the HBV X(HBx)gene plays a critical role in the molecular pathogenesis ofHBV-related HCC.We have investigated whether there are particular HBx gene mutations associated withHCC in patients from southern China.The HBx gene was examined in 51 paraffin-embedded tumor tissuesamples from patients with HCC and 25 serum samples from the HBV carrier by nested polymerase chainreaction(PCR),single-stranded conformational polymorphism and heteroduplex analysis.The HBx geneswith potentially important mutations from tumor tissue samples were cloned,sequenced and aligned withthe published HBx gene sequence.HBV genotypes in tumor tissue samples were analyzed by nested PCR.Analyses of HBx gene polymorphism showed that 31.3% of HBx gene fragments in tumor tissue sampleshad a special pattern.A common deletion at nt 382-400 of the HBx gene accompanied by 29 point mutationswas detected in four randomly selected tumor tissue samples with this pattern which caused a frame-shiftin the HBx open reading frame with a new stop codon at nt 1818,resulting in an HBx polypeptide chaintruncated at the C end in these cases.Among the four randomly selected samples,three were HBV genotypeB,and one was not detected by our present assay.In another tumor tissue sample,amplification of thefull-length HBx gene yielded a shorter fragment.Sequencing of this fragment revealed a 264 bp deletionbetween nt 1577 and 1840 of the HBV gene.These results suggest that HBx gene mutation occurs frequentlyin HCC samples,and the deletion at nt 382-400 of the HBx gene might play a role in carcinogenesis of HCCin southern China.     

Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues

Hepatocellular carcinoma (HCC) is a highly malignant tumor, and chronic infection with hepatitis B virus is one of its major risk factors. To identify the proteins involved in HCC carcinogenesis, we used two-dimensional fluorescence DIGE to study the differentially expressed proteins in tumor and adjacent nontumor tissue samples. Samples from 12 hepatitis B virus-associated HCC patients were analyzed. A total of 61 spots were significantly up-regulated (ratio >/= 2, p 相似文献   

Identification and extensive analysis of inverted-duplicated HBV integration in a human hepatocellular carcinoma cell line

Hepatitis B virus (HBV) DNA is often integrated into hepatocellular carcinoma (HCC). Although the relationship between HBV integration and HCC development has been widely studied, the role of HBV integration in HCC development is still not completely understood. In the present study, we constructed a pooled BAC library of 9 established cell lines derived from HCC patients with HBV infections. By amplifying viral genes and superpooling of BAC clones, we identified 2 clones harboring integrated HBV DNA. Screening of host-virus junctions by repeated sequencing revealed an HBV DNA integration site on chromosome 11q13 in the SNU-886 cell line. The structure and rearrangement of integrated HBV DNA were extensively analyzed. An inverted duplicated structure, with fusion of at least 2 HBV DNA molecules in opposite orientations, was identified in the region. The gene expression of cancer-related genes increased near the viral integration site in HCC cell line SNU-886.     

Quantitative analysis of phosphopeptides in search of the disease biomarker from the hepatocellular carcinoma specimen

Reversible phosphorylation of proteins is the most common PTM in cell‐signaling pathways. Despite this, high‐throughput methods for the systematic detection, identification, and quantification of phosphorylated peptides have yet to be developed. In this paper, we describe the establishment of an efficient online titaniuim dioxide (TiO₂)‐based 3‐D LC (strong cationic exchange/TiO₂/C18)‐MS³‐linear ion trap system, which provides fully automatic and highly efficient identification of phosphorylation sites in complex peptide mixtures. Using this system, low‐abundance phosphopeptides were isolated from cell lines, plasma, and tissue of healthy and hepatocellular carcinoma (HCC) patients. Furthermore, the phosphorylation sites were identified and the differences in phosphorylation levels between healthy and HCC patient specimens were quantified by labeling the phosphopeptides with isotopic analogs of amino acids (stable isotope labeling with amino acids in cell culture for HepG2 cells) or water (HO for tissues and plasma). Two examples of potential HCC phospho‐biomarkers including plectin‐1(phopho‐Ser‐4253) and alpha‐HS‐glycoprotein (phospho‐Ser 138 and 312) were identified by this analysis. Our results suggest that this comprehensive TiO₂‐based online‐3‐D LC‐MS³‐linear ion trap system with high‐throughput potential will be useful for the global profiling and quantification of the phosphoproteome and the identification of disease biomarkers.