Dataset Information

Whole Genome Scan for Pancreatic Cancer Risk in the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan)

ABSTRACT:

Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study expanded to include 8 case-controls studies. The study team includes scientists from the cohorts comprising the Consortium and NCI and from the PanC4 case-control studies.

The PanScan consortium has conducted two GWAS that have led to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The first two scans were conducted in 12 cohort studies and 8 case-control studies.

Initially, we genotyped 523,345 single nucleotide polymorphisms in 1,528 incident cases and 1,594 controls from nested case-control studies of 12 cohorts plus 368 cases and 345 controls from one hospital-based case-control study. Taqman replication of SNPs from the three most promising regions in the initial scan, as determined by rank p-values, was done in 2,457 cases and 2,654 controls from eight case-control studies that were part of the PanC4 consortium. A combined analysis identified an association between a locus on 9q34 and pancreatic cancer, the single nucleotide polymorphism rs505922 (P= 5.37 x 10^-8; multiplicative per-allele odds ratio (OR) 1.20; 95% CI 1.12-1.28), which maps to the first intron of the ABO blood group gene whose protein determines an individual's blood group (Amundadottir et al, Nature Genetics 2009, PMID: 19648918).

In PanScan 2, we conducted a combined analysis of 3,851 pancreatic cancer cases and 3,934 controls. These included 1896 cases and 1939 controls that were scanned in PanScan1 (above) and 1955 cases and 1995 controls that were newly scanned in PanScan2. The second GWAS did not include 502 cases and 659 controls that were part of the rapid replication. (Please see the attached table for the total number of subjects who were GWASed and included in PanScan1 and PanScan2). Three new regions were identified: chromosome 13q22.1 (rs9543325; P=3.27 x 10^-11; per-allele odds ratio (OR) 1.26; 95% CI 1.18-1.35); chromosome 1q32.1 in the NR5A2 gene (rs3790844; P=2.45 x 10^-10; per-allele OR 0.77; 95% CI 0.71-0.84); and chromosome 5p15.33 (rs401681 in the CLPTM1L and TERT region; P=3.66 x 10^-7; per-allele OR 1.19; 95% CI 1.11-1.27). The first two regions have not been identified in GWAS of cancer to date but the last region has been reported to be associated with risk of other malignancies (Petersen et al, Nature Genetics 2010, PMID: 20101243).

PROVIDER: phs000206.v3.p2 | EGA |

REPOSITORIES: EGA

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Publications

Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan).

Michaud Dominique S DS Vrieling Alina A Jiao Li L Mendelsohn Julie B JB Steplowski Emily E Lynch Shannon M SM Wactawski-Wende Jean J Arslan Alan A AA Bas Bueno-de-Mesquita H H Fuchs Charles S CS Gross Myron M Helzlsouer Kathy K Jacobs Eric J EJ Lacroix Andrea A Petersen Gloria G Zheng Wei W Allen Naomi N Ammundadottir Laufey L Bergmann Manuela M MM Boffetta Paolo P Buring Julie E JE Canzian Federico F Chanock Stephen J SJ Clavel-Chapelon Françoise F Clipp Sandra S Freiberg Matthew S MS Michael Gaziano J J Giovannucci Edward L EL Hankinson Susan S Hartge Patricia P Hoover Robert N RN Allan Hubbell F F Hunter David J DJ Hutchinson Amy A Jacobs Kevin K Kooperberg Charles C Kraft Peter P Manjer Jonas J Navarro Carmen C Peeters Petra H M PH Shu Xiao-Ou XO Stevens Victoria V Thomas Gilles G Tjønneland Anne A Tobias Geoffrey S GS Trichopoulos Dimitrios D Tumino Rosario R Vineis Paolo P Virtamo Jarmo J Wallace Robert R Wolpin Brian M BM Yu Kai K Zeleniuch-Jacquotte Anne A Stolzenberg-Solomon Rachael Z RZ

Cancer causes & control : CCC 20100407 8

The literature has consistently reported no association between low to moderate alcohol consumption and pancreatic cancer; however, a few studies have shown that high levels of intake may increase risk. Most single studies have limited power to detect associations even in the highest alcohol intake categories or to examine associations by alcohol type. We analyzed these associations using 1,530 pancreatic cancer cases and 1,530 controls from the Pancreatic Cancer Cohort Consortium (PanScan) nest ...[more]

PMID: 20373013

Publication: 1/5

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Project description:This study funded by the National Cancer Institute (NCI) involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to bladder cancer. This bladder GWAS has led to the discovery of three novel regions in the genome associated with bladder cancer risk. Cases were defined as individuals having histologically confirmed primary carcinoma of the urinary bladder, including carcinoma in situ (ICD-0-2 topography codes C67.0-C67.9 or ICD9 codes 188.1-188.9). Scan data were obtained from two case-control studies carried out in Spain and the United States (specifically, those in the Maine and Vermont components of the New England Bladder Cancer Study) and three prospective cohort studies in Finland and the United States (specifically Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, and The American Cancer Society Cancer Prevention Study II Nutrition Cohort). We used data from 591,637 single nucleotide polymorphisms 3,532 affected individuals (cases) and 5,119 controls of European descent and replication including 8382 cases and 48275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P ≈ 8 x 10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10-11) on maps to CCNE1 and rs11892031 (P = 1 x 10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3 (Rothman N et al., Nature Genetics, 2010, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20972438" target="_blank">20972438</a>). Through meta-analysis with the MD Anderson Texas Bladder Cancer Study (TXBCS), we also identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22) (Garcia-Closas M et al, Human Molecular Genetics, 2011) For NCI-GWAS2, we performed genotyping on cases and controls for the New Hampshire component of the New England Bladder Cancer Study (NEBCS-NH). For the majority of new bladder cancer cases, we genotyped only cases from four case-control studies, the Los Angeles Bladder Cancer Study (LABCS), the French Center for Research on Prostate Diseases (CeRePP), the French Bladder Study (FBCS) and the Brescia Bladder Cancer Study (BBCS). We used existing control data from four cohort studies already genotyped and subjected to rigorous quality control metrics: the European Prospective Investigation Into Cancer and Nutrition Study (EPIC), Womens Health Initiative (WHI), Health Professionals Follow-up Study (HPFS), Nurses Health Study (NHS), which have been a part of Cancer Genetic Markers of Susceptibility (CGEMS). Meta-analysis of NCI-GWAS1, NCI-GWAS2 and a previously reported GWAS TXBCS-GWAS along with taqman replication, identified two new loci: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 X 10(-7)); these require further studies for confirmation (Figueroa J et al, Human Molecular Genetics, 2013).

Project description:Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study (GWAS) of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study was expanded to include 8 case-control studies. The study team includes scientists from the cohorts comprising the Consortium, the NCI and the Pancreatic Cancer Case Control Consortium (PanC4). PanScan I and II were conducted in 12 cohort studies and 8 case-control studies, leading to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The third phase of PanScan (PanScan III) was conducted using recently identified incident pancreatic cancer cases drawn from fourteen cohorts from the cohort consortium, including nine prospective cohorts who participated in PanScan I, and five newly joined cohorts. The nine cohort studies that participated in PanScan I and had new genotyping of cases in PanScan III include ATBC, CPS-II, EPIC, HPFS, NHS, PHS, PLCO, SMWHS, and WHI; the five newly joined cohort studies include the Agricultural Health Study (AHS), the Multiethnic Cohort Study (MEC), the Melbourne Collaborative Cohort Study (MCCS), the Vitamins and Lifestyle Study (VITAL), and Selenium and Vitamin E Cancer Prevention Trial (SELECT). In addition to the cases from cohorts, we also included cases from the Gastrointestinal Cancer Clinic of Dana-Farber Cancer Institute Study (DFCI-GCC); from the University Hospital in Heidelberg, Germany, which is part of a larger European clinical case-control study (PANDoRA); and from clinic-based cases from eastern Spain (PANKRAS-II). The dbGaP datasets available include all subjects previously made available from PanScan I and II (phs000206.v4.p3), plus 1,582 new incident pancreatic cancer cases of European descent from prospective cohorts, case-control studies or case series (genotyped as part of PanScan III). Also included are 61 pancreatic cancer cases and 67 control subjects from PanScan I as well as 173 pancreatic cancer cases from PanScan III of Asian ancestry from the Shanghai Men's and Women's Health Study (Supplemental Table 10, Wolpin et al. (Nat Genet, 2014)). The control population used in the analysis for the Wolpin et al. manuscript included cancer-free individuals from the prospective cohorts that contributed pancreatic cancer cases to PanScan III and controls from the Spanish Bladder Cancer SBC/EPICURO study that were previously genotyped using the OmniExpress, Omni 1M or Omni 2.5M SNP arrays. The data from these control subjects were posted to dbGaP under the GWAS in which they were initially genotyped and will not be made available in duplicate under this dbGaP study.

Project description:BACKGROUND: There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing.METHODS: Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with acute viral infections, including COVID-19, bacterial infections, inflammatory conditions and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined.FINDINGS: 3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral with 101 non-viral cases in the discovery cohort, ddhC was the most differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral with 40 bacterial cases, generating an AUC of 0.81 (95% CI: 0.708-0.915). Transcripts of viperin and CMPK2, enzymes responsible for ddhCTP synthesis, were amongst the 5 genes most highly correlated with ddhC abundance.CONCLUSIONS: The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes, viperin and CMPK2 are implicated in ddhC production in vivo. These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness and acute infection management.FUNDING: National Institute for Health Research Imperial Biomedical Research Centre; Medical Research Council.

Dataset Information

Whole Genome Scan for Pancreatic Cancer Risk in the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan)

Publications

Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan).

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