ABSTRACT
BACKGROUND: Human Cub and Sushi Multiple Domains 1 (CSMD1) is a novel candidate tumor-suppressor gene that codes for multiple domains, including complement regulatory and adhesion proteins, and has recently been shown to have alterations in multiple cancers. We investigated CSMD1 in esophageal squamous cell carcinoma (ESCC) by performing an integrated analysis on somatic copy number alterations (CNAs), including copy-number gain or loss, allelic imbalance (AI), loss of heterozygosity (LOH), and the expressions of mRNA and its target miRNAs on specimens from the same patients with ESCC. RESULTS: (i) Two-thirds of ESCC patients had all three types of alterations studied-somatic DNA alterations in 70%, and abnormal expressions of CSMD1 RNA in 69% and in target miRNAs in 66%; patterns among these alterations were complex. (ii) In total, 97% of 888 CSMD1 SNPs studied showed somatic DNA alterations, with most located near exons 4-11, 24-25, 39-40, 55-56, and 69-70. (iii) In total, 68% of SNPs with a CNA were correlated with expression of CSMD1. (iv) A total of 33 correlations between non-coding SNPs and expression of CSMD1 target miRs were found. CONCLUSIONS: Our results indicate that the CSMD1 gene may play a role in ESCC through complex patterns of DNA alterations and RNA and miRNA expressions. Alterations in some somatic SNPs in non-coding regions of CSMD1 appear to influence expression of this gene and its target miRNAs.
ABSTRACT
We integrated ESCC expression and GWAS genotyping, to investigate eQTL and somatic DNA segment alterations, including somatic copy number alteration, allelic imbalance (AI), and loss of heterozygosity (LOH) in ESCC. First, in eQTL analysis, we used a classical approach based on genotype data from GWAS and expression signals in normal tissue samples, and then used a modified approach based on fold change in the tumor vs. normal samples. We focused on the genes in three pathways: inflammation, DNA repair, and immunity. Among the significant (p < 0.05) SNP-probe pairs from classical and modified eQTL analyses, 24 genes were shared by the two approaches, including 18 genes that showed the same numbers of SNPs and probes and 6 genes that had the different numbers of SNPs and probes. For these 18 genes, we found 28 SNP−probe pairs were correlated in opposite directions in the two approaches, indicating an intriguing difference between the classical and modified eQTL approaches. Second, we analyzed the somatic DNA segment alterations. Across the 24 genes, abnormal gene expression on mRNA arrays was seen in 19−95% of cases and 26−78% showed somatic DNA segment alterations on Affymetrix GeneChip Human Mapping Arrays. The results suggested that this strategy could identify gene expression and somatic DNA segment alterations for biological markers (genes) by combining classical and modified eQTLs and somatic DNA evaluation on SNP arrays. Thus, this study approach may allow us to understand functionality indicative of potentially relevant biomarkers in ESCC.
ABSTRACT
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC. METHODS: We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics. RESULTS: Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51-0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L. CONCLUSIONS: Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.
Subject(s)
Biomarkers, Tumor/metabolism , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Gene Expression Regulation, Neoplastic , Genome, Human , MicroRNAs/genetics , RNA, Messenger/metabolism , Adult , Aged , Biomarkers, Tumor/genetics , Case-Control Studies , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/surgery , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Male , MicroRNAs/metabolism , Middle Aged , Prognosis , RNA, Messenger/genetics , Survival RateABSTRACT
OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.
Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/blood , Early Detection of Cancer , Esophageal Neoplasms/diagnosis , Inflammation Mediators/blood , Adenocarcinoma/epidemiology , Adenocarcinoma/metabolism , Adenocarcinoma/surgery , Aged , Body Mass Index , Consensus , Cross-Sectional Studies , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/surgery , Female , Humans , Incidence , Logistic Models , Male , Middle Aged , Obesity/epidemiology , Predictive Value of Tests , Prognosis , Prospective Studies , Smoking/epidemiologyABSTRACT
Eleven high-evidence single-nucleotide polymorphisms (SNPs) at nine loci for gastric cancer (GC) risk were reported, but their associations with survival remain unknown. In this study, we examined associations between SNP and GC survival by anatomic location and histology among 1147 incident cases from the Shanxi Upper Gastrointestinal Genetics Project. We further examined whether SNPs were expression quantitative trait loci in normal and tumor gastric tissues, and whether tumor versus normal somatic mRNA differences in 126 cases were associated with survival. No SNPs were associated with GC survival overall. However, subtype-specific associations were observed for gastric cardia adenocarcinomas at MUC1/TRIM46/1q22 rs2070803 [HRAA versus GA+GG = 2.16; 95% confidence interval (CI) = 1.24-3.78; P = 0.0068] and LTA/TNF/6p21.33 rs1799724 (HRTT+CT versus CC = 1.30; 95% CI = 1.07-1.57; P = 0.0077), and for diffuse-type GC at PSCA/8q24.3 rs2294008 (HRTT versus CT+CC = 1.99; 95% CI = 1.33-2.97; P = 7.8E-04). Rs2294008T was a cis-expression quantitative trait loci for PSCA, upregulating mRNA in normal gastric (ß = 0.60; P = 5.7E-21) and GC (ß = 0.30; P = 0.0089) tissues. Cases in the highest quartile (the smallest downregulation of tumor PSCA) had shortest survival than cases with the most downregulated PSCA (median survival of 0.47 years in the highest quartile versus 3.73 years in the lowest quartile; hazard ratio = 9.70; 95% CI = 2.46-38.4; P = 0.0012). Less striking effects for mRNA levels were observed for MTX1 at 1q22 in gastric cardia adenocarcinoma and for JRK at 8q24.3 in diffuse GC. Our results suggest three high-evidence GC risk loci have prognostic importance in GC subtypes. Future studies in well-characterized independent populations are warranted to validate our findings and further investigate the clinical utility of these variants in predicting GC prognosis.
Subject(s)
Gene Expression/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Stomach Neoplasms/etiology , Stomach Neoplasms/genetics , Adenocarcinoma/etiology , Adenocarcinoma/genetics , Asian People/genetics , Case-Control Studies , Down-Regulation/genetics , Female , Genome-Wide Association Study/methods , Genotype , Humans , Male , Middle Aged , Prognosis , RNA, Messenger/genetics , Risk Factors , Up-Regulation/geneticsABSTRACT
Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10-5 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10-6 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.
Subject(s)
Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/genetics , Gastrointestinal Neoplasms/genetics , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide , Asian People/genetics , China , Female , Follow-Up Studies , Genetic Loci , Genetic Predisposition to Disease , Humans , Male , Neoplasm StagingABSTRACT
The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) in 2008 to develop the infrastructure needed to link the contents of the NHLBI Biorepository and the NHLBI Data Repository, and to promote the utilization of these scientific resources by the broader research community. Program utilization metrics were developed to measure the impact of BioLINCC on Biorepository access by researchers, including visibility, program efficiency, user characteristics, scientific impact, and research types. Input data elements were defined and are continually populated as requests move through the process of initiation through fulfillment and publication. This paper reviews the elements of the tracking metrics which were developed for BioLINCC and reports the results for the first six on-line years of the program.
Subject(s)
Biological Specimen Banks/organization & administration , Specimen Handling/methods , Humans , Internet , National Heart, Lung, and Blood Institute (U.S.) , National Institutes of Health (U.S.) , Program Development , United StatesABSTRACT
BACKGROUND: Research on data sharing from clinical trials has focused on elucidating perceptions, barriers, and attitudes among trialists and study participants with respect to sharing data. However, little information exists regarding utilization or associated publication of articles once clinical trial data have been widely shared. METHODS: We analyzed administrative records of investigator requests for data access, linked publications, and bibliometrics to describe the use of the National Heart, Lung, and Blood Institute data repository. RESULTS: From January 2000 through May 2016, a total of 370 investigators requested data from 1 or more clinical trials. Requests for trial data have been increasing, with 195 investigators (53%) initiating requests during the last 4.4 years of the study period. The predominant reason for requesting data was post hoc secondary analysis of new questions (72%), followed by analytic or statistical approaches to clinical trials (9%) and meta-analyses or pooled study research (7%). Of 172 requests with online project descriptions, only 2 requests were initiated for reanalysis of primary-outcome findings. Data from 88 of 100 available clinical trials were requested at least once, and the median time from repository availability to first request was 235 days. A total of 277 articles were published on the basis of data from 47 trials. Citation metrics from 224 articles indicated that half of the publications have cumulative citations that rank in the top 34% normalized for subject category and year of publication. CONCLUSIONS: Demand for trial data for secondary analysis has been increasing. Requesting data for the a priori purpose of reanalysis or verification of original findings was rare.
Subject(s)
Clinical Trials as Topic , Datasets as Topic/statistics & numerical data , Information Dissemination , National Heart, Lung, and Blood Institute (U.S.) , Bibliometrics , Humans , Kaplan-Meier Estimate , Observational Studies as Topic , Periodicals as Topic/statistics & numerical data , United StatesABSTRACT
INTRODUCTION: Reducing costs by improving storage efficiency has been a focus of the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen Repository (Biorepository) and Biologic Specimen and Data Repositories Information Coordinating Center (BioLINCC) programs for several years. METHODS: Study specimen profiles were compiled using the BioLINCC collection catalog. Cost assessments and calculations on the return on investments to consolidate or reduce a collection, were developed and implemented. RESULTS: Over the course of 8 months, the NHLBI Biorepository evaluated 35 collections that consisted of 1.8 million biospecimens. A total of 23 collections were selected for consolidation, with a total of 1.2 million specimens located in 21,355 storage boxes. The consolidation resulted in a savings of 4055 boxes of various sizes and 10.2 mechanical freezers (â¼275 cubic feet) worth of space. CONCLUSION: As storage costs in a biorepository increase over time, the development and use of information technology tools to assess the potential advantage and feasiblity of vial consolidation can reduce maintenance expenses.
Subject(s)
Biological Specimen Banks , Models, Theoretical , Biological Specimen Banks/economics , Humans , Investments , National Heart, Lung, and Blood Institute (U.S.) , United StatesABSTRACT
OBJECTIVE: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. DESIGN: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. RESULTS: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10-11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20×10-4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10-19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10-17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47×10-8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. CONCLUSION: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.
Subject(s)
Adenocarcinoma/genetics , Asian People/genetics , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 5 , Genetic Predisposition to Disease , Stomach Neoplasms/genetics , China , Genetic Loci , Genome-Wide Association Study , Genotype , Humans , Polymorphism, Single Nucleotide , RNA, Untranslated/geneticsABSTRACT
Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.
Subject(s)
Adenocarcinoma/epidemiology , Adenocarcinoma/etiology , Barrett Esophagus/epidemiology , Barrett Esophagus/etiology , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/etiology , Leukocytes/metabolism , Telomere/genetics , Female , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/epidemiology , Gastroesophageal Reflux/etiology , Humans , Male , Odds Ratio , Population Surveillance , Prevalence , RiskABSTRACT
Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714-23. ©2016 AACR.
Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Genomics/methods , Stomach Neoplasms/genetics , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Female , Genetic Predisposition to Disease , Humans , Male , Stomach Neoplasms/pathologyABSTRACT
OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is endemic in east Africa and is a leading cause of cancer death among Kenyans. The asymptomatic precursor lesion of ESCC is esophageal squamous dysplasia (ESD). We aimed to determine the prevalence of ESD in asymptomatic adult residents of southwestern Kenya. METHODS: In this prospective, community-based, cross-sectional study, 305 asymptomatic adult residents completed questionnaires and underwent video endoscopy with Lugol's iodine chromoendoscopy and mucosal biopsy for detection of ESD. RESULTS: Study procedures were well tolerated, and there were no adverse events. The overall prevalence of ESD was 14.4% (95% confidence interval (CI): 10-19%), including 11.5% with low-grade dysplasia and 2.9% with high-grade dysplasia. The prevalence of ESD was >20% among men aged >50 years and women aged >60 years. Residence location was significantly associated with ESD (Zone A adjusted odds ratio (OR) 2.37, 95% CI: 1.06-5.30 and Zone B adjusted OR 2.72, 95% CI: 1.12-6.57, compared with Zone C). Iodine chromoendoscopy with biopsy of unstained lesions was more sensitive than white-light endoscopy or random mucosal biopsy for detection of ESD and had 67% sensitivity and 70% specificity. CONCLUSIONS: ESD is common among asymptomatic residents of southwestern Kenya and is especially prevalent in persons aged >50 years and those living in particular local regions. Lugol's iodine chromoendoscopy is necessary for detection of most ESD but has only moderate sensitivity and specificity in this setting. Screening for ESD is warranted in this high-risk population, and endoscopic screening of Kenyans is feasible, safe, and acceptable, but more accurate and less invasive screening tests are needed.
Subject(s)
Esophagus/pathology , Precancerous Conditions/pathology , Adult , Biopsy , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , Cross-Sectional Studies , Early Detection of Cancer , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Esophagoscopy , Female , Humans , Iodides , Kenya/epidemiology , Male , Middle Aged , Precancerous Conditions/epidemiology , Prevalence , Prospective Studies , Risk Factors , Sensitivity and Specificity , Surveys and QuestionnairesABSTRACT
OBJECTIVE: Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia. DESIGN: Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non-cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing. RESULTS: We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36×10(-12)) and non-cardia cancers (p=2.42×10(-23)) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50×10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47×10(-2)). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59×10(-8) for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer. CONCLUSIONS: Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach.
Subject(s)
AMP-Activated Protein Kinases/genetics , Adenocarcinoma , Cardia , Intracellular Signaling Peptides and Proteins/genetics , Mucin-1/genetics , Stomach Neoplasms , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Asian People , Case-Control Studies , China/epidemiology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide , Republic of Korea/epidemiology , Stomach Neoplasms/epidemiology , Stomach Neoplasms/genetics , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. METHOD: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. RESULTS: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P = .75E-14). CONCLUSION: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs.
Subject(s)
Carcinoma, Squamous Cell/genetics , Caspase 8/genetics , Esophageal Neoplasms/genetics , Isocitrate Dehydrogenase/genetics , Polymorphism, Single Nucleotide , Signal Transduction/genetics , Asian People/genetics , China , Esophageal Squamous Cell Carcinoma , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Logistic Models , Quantitative Trait LociABSTRACT
BACKGROUND: Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors. In the current study we focus on biallelic loss and its relation to expression of mRNA and miRNA in ESCC using results from 500 K SNP, mRNA, and miRNA arrays in 30 cases from a high-risk region of China. RESULTS: (i) Biallelic loss was uncommon but when it occurred it exhibited a consistent pattern: only 77 genes (<0.5%) showed biallelic loss in at least 10% of ESCC samples, but nearly all of these genes were concentrated on just four chromosomal arms (i.e., 42 genes on 3p, 14 genes on 9p, 10 genes on 5q, and seven genes on 4p). (ii) Biallelic loss was associated with lower mRNA expression: 52 of the 77 genes also had RNA expression data, and 41 (79%) showed lower expression levels in cases with biallelic loss compared to those without. (iii) The relation of biallelic loss to miRNA expression was less clear but appeared to favor higher miRNA levels: of 60 miRNA-target gene pairs, 34 pairs (57%) had higher miRNA expression with biallelic loss than without, while 26 pairs (43%) had lower miRNA expression. (iv) Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex. Biallelic loss was most commonly associated with a pattern of elevated miRNA and reduced mRNA (43%), but a pattern of both reduced miRNA and mRNA was also common (35%). CONCLUSION: Our results indicate that biallelic loss in ESCC is uncommon, but when it occurs it is localized to a few specific chromosome regions and is associated with reduced mRNA expression of affected genes. The effect of biallelic loss on miRNA expression and on the relation between miRNA and mRNA expressions was complex.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Genetic Association Studies , MicroRNAs/metabolism , RNA, Messenger/metabolism , Adult , Aged , Alleles , China , Chromosomes, Human , Esophageal Squamous Cell Carcinoma , Female , Genomic Instability , Humans , Male , Middle Aged , Neoplasm Grading , TranscriptomeABSTRACT
The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established a Biorepository in 1976 that initially archived biospecimens from population-based blood product safety surveys. It was later expanded to biospecimens from clinical and epidemiological studies in heart, lung, and blood disorders. The NHLBI also established a Data Repository in 2000 to store and distribute study data from NHLBI-sponsored research. The NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) was established in 2008 to develop the infrastructure needed to link the contents of these two related NHLBI Repositories, facilitate access to repository resources, and streamline request processes. Three key program subcomponents were developed simultaneously: 1) the linkage of biospecimen electronic inventory records with their clinical or characterization data; 2) the development and implementation of a website with both public-facing information and private processing workspaces; and 3) the development of processes to maximize efficiency via a web-based system while maintaining workflow control, document tracking, and secure processes. The BioLINCC website was launched on October 1, 2009 with eight biospecimen collections and data from 72 research studies. By the end of the fourth online year, 38 biospecimen collections were linked and posted, and data from 108 research studies had been made available for request. The number of registered users by the end of the fourth online year approached 2600, and continues to show a trend towards an increasing rate of new users per year. BioLINCC has fulfilled 381 requests comprising 851 data collections, as well as 600 teaching dataset requests and 75 data renewal agreements. 154 biospecimen requests comprising 147,388 biospecimens were fulfilled or actively in process. We conclude that the BioLINCC program has been successful in its goal to increase the visibility and utilization of NHLBI biospecimen and data repository resources.
Subject(s)
Biological Specimen Banks , Specimen Handling/methods , Biological Products , Data Collection , Humans , Internet , National Heart, Lung, and Blood Institute (U.S.) , Program Development , Software , United StatesABSTRACT
BACKGROUND: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. METHODS: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses. RESULTS: Suggestive pathway-based associations were observed for the overall epigenetic (P-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value(GENE )< 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues. CONCLUSIONS: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Squamous Cell/genetics , DNA Methylation , Epigenesis, Genetic , Esophageal Neoplasms/genetics , Stomach Neoplasms/genetics , Aged , Asian People/genetics , Case-Control Studies , China , Esophageal Squamous Cell Carcinoma , Female , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
BACKGROUND & AIMS: Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. METHODS: We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 174 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by enzyme-linked immunosorbent assay. We also calculated free estradiol, free testosterone, and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index, heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). RESULTS: Levels of free testosterone and free DHT were associated positively with BE risk; patients in the highest quartile for these hormones were most likely to have BE (free testosterone: OR, 5.36; 95% CI, 2.21-13.03; P = .0002; free DHT: OR, 4.25; 95% CI, 1.87-9.66; P = .001). Level of estrone sulfate was associated inversely with BE risk (P for trend = .02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. CONCLUSIONS: In an analysis of men, levels of free testosterone and free DHT were significantly associated with BE.
Subject(s)
Barrett Esophagus/pathology , Gonadal Steroid Hormones/blood , Adult , Aged , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Mass Spectrometry , Middle Aged , Sex Hormone-Binding Globulin/analysisABSTRACT
BACKGROUND: Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival. METHODS: PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124). RESULTS: Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; Ptrend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; Ptrend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; Ptrend = 0.04). CONCLUSIONS: Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis. IMPACT: A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation.