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8 results on '"Childs, Erica J."'

1. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Author

Mocci E, Kundu P, Wheeler W, Arslan AA, Beane-Freeman LE, Bracci PM, Brennan P, Canzian F, Du M, Gallinger S, Giles GG, Goodman PJ, Kooperberg C, Le Marchand L, Neale RE, Shu XO, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, Babic A, Bamlet WR, Berndt SI, Blackford AL, Bueno-de-Mesquita B, Buring JE, Campa D, Chanock SJ, Childs EJ, Duell EJ, Fuchs CS, Gaziano JM, Giovannucci EL, Goggins MG, Hartge P, Hassan MM, Holly EA, Hoover RN, Hung RJ, Kurtz RC, Lee IM, Malats N, Milne RL, Ng K, Oberg AL, Panico S, Peters U, Porta M, Rabe KG, Riboli E, Rothman N, Scelo G, Sesso HD, Silverman DT, Stevens VL, Strobel O, Thompson IM Jr, Tjonneland A, Trichopoulou A, Van Den Eeden SK, Wactawski-Wende J, Wentzensen N, Wilkens LR, Yu H, Yuan F, Zeleniuch-Jacquotte A, Amundadottir LT, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Kraft P, Chatterjee N, Klein AP, and Stolzenberg-Solomon R

Subjects
Carcinoma, Pancreatic Ductal etiology, Carcinoma, Pancreatic Ductal metabolism, Cyclin T genetics, Genome-Wide Association Study, Genotype, Humans, Membrane Proteins genetics, Pancreatic Neoplasms etiology, Pancreatic Neoplasms metabolism, Risk Factors, Smoking genetics, Carcinoma, Pancreatic Ductal pathology, Chromosomes, Human, Pair 2 genetics, Genetic Predisposition to Disease, Pancreatic Neoplasms pathology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Smoking adverse effects
Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10 -8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10 -9 ). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention., (©2021 American Association for Cancer Research.)

Published
2021
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2. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.

Author

Childs EJ, Mocci E, Campa D, Bracci PM, Gallinger S, Goggins M, Li D, Neale RE, Olson SH, Scelo G, Amundadottir LT, Bamlet WR, Bijlsma MF, Blackford A, Borges M, Brennan P, Brenner H, Bueno-de-Mesquita HB, Canzian F, Capurso G, Cavestro GM, Chaffee KG, Chanock SJ, Cleary SP, Cotterchio M, Foretova L, Fuchs C, Funel N, Gazouli M, Hassan M, Herman JM, Holcatova I, Holly EA, Hoover RN, Hung RJ, Janout V, Key TJ, Kupcinskas J, Kurtz RC, Landi S, Lu L, Malecka-Panas E, Mambrini A, Mohelnikova-Duchonova B, Neoptolemos JP, Oberg AL, Orlow I, Pasquali C, Pezzilli R, Rizzato C, Saldia A, Scarpa A, Stolzenberg-Solomon RZ, Strobel O, Tavano F, Vashist YK, Vodicka P, Wolpin BM, Yu H, Petersen GM, Risch HA, and Klein AP

Subjects
Aged, Australia, Europe, Female, Gene Frequency, Genetic Loci genetics, Genome-Wide Association Study methods, Genotype, Humans, Male, Middle Aged, North America, Risk Factors, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 2 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 7 genetics, Genetic Predisposition to Disease genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Published
2015
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3. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer

Author

Walsh, Naomi, Zhang, Han, Hyland, Paula L, Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J, Collins, Irene, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Brennan, Paul, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hung, Rayjean J, Kooperberg, Charles, Kurtz, Robert C, Malats, Núria, LeMarchand, Loic, Neale, Rachel E, Olson, Sara H, Scelo, Ghislaine, Shu, Xiao O, Van Den Eeden, Stephen K, Visvanathan, Kala, White, Emily, Zheng, Wei, PanScan and PanC4 consortia, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R, Berndt, Sonja I, Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-de-Mesquita, Bas, Buring, Julie, Chaffee, Kari G, Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M Gaziano, J Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Janout, Vladimir, Klein, Eric A, Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L, Oberg, Ann L, Orlow, Irene, Patel, Alpa V, Peters, Ulrike, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Sesso, Howard D, Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D, Tobias, Geoffrey S, Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J, Petersen, Gloria M, Wolpin, Brian M, Risch, Harvey A, Amundadottir, Laufey T, Yu, Kai, Klein, Alison P, Stolzenberg-Solomon, Rachael Z, Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Pancreatic Neoplasms, Models, Statistical, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

Published
2018

4. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, Alison P, Wolpin, Brian M, Risch, Harvey A, Stolzenberg-Solomon, Rachael Z, Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J, Hoskins, Jason W, Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A, Babic, Ana, Bamlet, William R, Beane-Freeman, Laura, Berndt, Sonja I, Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M, Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Bas, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G, Chung, Charles C, Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J, Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, M Gaziano, J Michael, Gazouli, Maria, Giles, Graham G, Giovannucci, Edward, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Hung, Rayjean J, Jacobs, Eric J, Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H, Kupcinskas, Juozas, Kurtz, Robert J, Laheru, Daniel, Landi, Stefano, Lawlor, Rita T, Lee, I-Min, LeMarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Mohelníková-Duchoňová, Beatrice, Neale, Rachel E, Neoptolemos, John P, Oberg, Ann L, Olson, Sara H, Orlow, Irene, Pasquali, Claudio, Patel, Alpa V, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D, Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P, Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D, Tobias, Geoffrey S, Van Den Eeden, Stephen K, Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M, and Amundadottir, Laufey T

Subjects
Intracellular Signaling Peptides and Proteins, Proteins, Polymorphism, Single Nucleotide, 3. Good health, Pancreatic Neoplasms, Repressor Proteins, Hepatocyte Nuclear Factor 4, Tensins, Databases, Genetic, Humans, Intercellular Signaling Peptides and Proteins, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

5. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer

Author

Walsh, Naomi, Zhang, Han, Hyland, Paula L, Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J, Collins, Irene, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Brennan, Paul, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hung, Rayjean J, Kooperberg, Charles, Kurtz, Robert C, Malats, Núria, LeMarchand, Loic, Neale, Rachel E, Olson, Sara H, Scelo, Ghislaine, Shu, Xiao O, Van Den Eeden, Stephen K, Visvanathan, Kala, White, Emily, Zheng, Wei, PanScan And PanC4 Consortia, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R, Berndt, Sonja I, Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-De-Mesquita, Bas, Buring, Julie, Chaffee, Kari G, Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M Gaziano, J Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Janout, Vladimir, Klein, Eric A, Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L, Oberg, Ann L, Orlow, Irene, Patel, Alpa V, Peters, Ulrike, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Sesso, Howard D, Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D, Tobias, Geoffrey S, Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J, Petersen, Gloria M, Wolpin, Brian M, Risch, Harvey A, Amundadottir, Laufey T, Yu, Kai, Klein, Alison P, and Stolzenberg-Solomon, Rachael Z

Subjects
Pancreatic Neoplasms, Models, Statistical, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, 3. Good health, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified., This work was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. This publication has emanated from research supported in part by a Grant from Science Foundation Ireland under Grant number [15/SIRG/3482](NW) and Health Research Board/Irish Cancer Society (CPFPR-2012–2)(NW). This work was also supported by RO1 CA154823 and federal funds from the National Cancer Institute (NCI), US National Institutes of Health, under contract number HHSN261200800001E. Please see the Supplementary Materials (available online) for a complete list of funding acknowledgments

6. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetrius, Andreotti, Gabriella, Brais, Lauren, Bueno-De-Mesquita, H Bas, Basso, Daniela, Berndt, Sonja I, Boutron-Ruault, Marie-Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka-Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Krogh, Vittorio, Kupcinskas, Juozas, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra HM, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao-Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka-Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Vashist, Yogesh, Vodicka, Pavel, Wactawski-Wende, Jean, Wentzensen, Nicolas, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Kooperberg, Charles, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charles, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg-Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, and Amundadottir, Laufey T

Subjects
Genotype, NR5A2, pancreatic cancer, Datasets as Topic, imputation, Polymorphism, Single Nucleotide, 3. Good health, Pancreatic Neoplasms, fine-mapping, Chromosomes, Human, Pair 1, GWAS, Chromosomes, Human, Pair 5, Humans, Genetic Predisposition to Disease, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

7. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.

Subjects
0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract

Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

8. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Christopher A. Haiman, Herbert Yu, Lauren K. Brais, Gabriele Capurso, Eric J. Duell, Michelle Cotterchio, Núria Malats, Beatrice Mohelníková-Duchoňová, Claudio Pasquali, Gary E. Goodman, Giulia Martina Cavestro, Kala Visvanathan, Sean P. Cleary, Jill P. Smith, Jean Wactawski-Wende, Rita T. Lawlor, Gianluca Severi, J. Michael Gaziano, Kathy J. Helzlsouer, Charles C. Chung, Harvey A. Risch, Stephen K. Van Den Eeden, Elizabeth A. Holly, Bas Bueno-de-Mesquita, Patricia Hartge, Fei Chen, Mark D. Thornquist, Hermann Brenner, Ulrike Peters, Ghislaine Scelo, Steven Gallinger, Sonja I. Berndt, Howard D. Sesso, Lenka Foretova, Laufey T. Amundadottir, Mingfeng Zhang, Federico Canzian, Rudolf Kaaks, Stephen J. Chanock, Nicolas Wentzensen, Ann L. Oberg, Eric J. Jacobs, Peter Kraft, Rayjean J. Hung, Evelina Mocci, Maria Gazouli, Francesca Tavano, Michael Borges, Zhaoming Wang, Alan A. Arslan, Wei Zheng, Ayelet Borgida, Paige M. Bracci, Jason W. Hoskins, William R. Bamlet, Juozas Kupcinskas, Joseph M. Herman, Demetrius Albanes, Charles S. Fuchs, Nathaniel Rothman, Niccola Funel, Pavel Soucek, Edward Giovannucci, Paul Brennan, Thilo Hackert, Jun Zhong, Manolis Kogevinas, Robert N. Hoover, Michael Goggins, Amanda L. Blackford, Robert J. Kurtz, Malin Sund, Roger L. Milne, Stefano Landi, Francisco X. Real, Emily White, Miquel Porta, Ivana Holcatova, Kari G. Chaffee, Vladimir Janout, Charles Kooperberg, Péter Hegyi, Frederike Dijk, Yogesh K. Vashist, Andrea Mambrini, Matthew H. Kulke, I. Min Lee, Kai Yu, Alison P. Klein, Phyllis J. Goodman, Donghui Li, Julie E. Buring, Debra T. Silverman, Ana Babic, John P. Neoptolemos, Erica J. Childs, Alpa V. Patel, Sara H. Olson, Brian M. Wolpin, Krzysztof Jamroziak, Gloria M. Petersen, Xiao-Ou Shu, Renata Talar-Wojnarowska, Rachel E. Neale, Daniel A. Laheru, Kay-Tee Khaw, Eric A. Klein, Ashley Jermusyk, Graham G. Giles, Daniele Campa, Laura Beane-Freeman, Rachael Z. Stolzenberg-Solomon, Raffaele Pezzilli, Geoffrey S. Tobias, Pavel Vodicka, Irene Orlow, Anne Zeleniuch-Jacquotte, Ofure Obazee, Satu Männistö, Lingeng Lu, Manal Hasan, Loic LeMarchand, Gabriella Andreotti, CCA - Cancer biology and immunology, Pathology, Lung Cancer Research Foundation, Sol Goldman Pancreas Cancer Research Center, Geoffrey Beene Foundation, Arnold and Arlene Goldstein Family Foundation, National Health and Medical Research Council (Australia), Czech Science Foundation, Joan Rombauer Pancreatic Cancer Foundation, NIH - National Cancer Institute (NCI) (Estados Unidos), Instituto de Salud Carlos III, Ministerio de Ciencia y Tecnología (España), Red Temática de Investigación Cooperativa en Cáncer (España), Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública), Mocci, Evelina [0000-0002-7101-9556], Canzian, Federico [0000-0002-4261-4583], Chaffee, Kari G [0000-0002-7313-1875], Dijk, Frederike [0000-0003-3970-6601], Gazouli, Maria [0000-0002-3295-6811], Jacobs, Eric J [0000-0002-8458-7659], Klein, Eric A [0000-0002-1783-0698], Lu, Lingeng [0000-0001-9871-0809], Malats, Núria [0000-0003-2538-3784], Milne, Roger L [0000-0001-5764-7268], Neoptolemos, John P [0000-0002-6201-7399], Oberg, Ann L [0000-0003-2539-9807], Pezzilli, Raffaele [0000-0001-9827-7451], Porta, Miquel [0000-0003-1684-7428], Real, Francisco X [0000-0001-9501-498X], Sund, Malin [0000-0002-7516-9543], Tobias, Geoffrey S [0000-0002-2878-8253], Van Den Eeden, Stephen K [0000-0002-5599-8387], Yu, Herbert [0000-0003-3950-4815], Zheng, Wei [0000-0003-1226-070X], Obazee, Ofure [0000-0001-8791-5008], Amundadottir, Laufey T [0000-0003-1859-8971], Apollo - University of Cambridge Repository, Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetriu, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Ba, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charle, Funel, Niccola, Gallinger, Steven, Gaziano, J. Michael M., Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manoli, Kooperberg, Charle, Kulke, Matthew H., Kupcinskas, Juoza, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I. -Min, Lemarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelníková-Duchoňová, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicola, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., and Amundadottir, Laufey T.

Subjects
0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Pancreatic disease, Chemistry(all), General Physics and Astronomy, Genome-wide association study, Disease, Biochemistry, DISEASE, Tensins, Databases, Genetic, IMPUTATION, 03.02. Klinikai orvostan, lcsh:Science, Càncer, Pancreas cancer, GENE-EXPRESSION, Cancer, RISK, Multidisciplinary, Chemistry (all), Pancreatic Neoplasm, Intracellular Signaling Peptides and Proteins, HNF1B, 3. Good health, TRANSCRIPTION FACTORS, Hepatocyte Nuclear Factor 4, Intercellular Signaling Peptides and Proteins, Human, Carcinoma, Pancreatic Ductal, medicine.medical_specialty, Science, Physics and Astronomy(all), Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), Cancer epidemiology, Pancreatic cancer, Internal medicine, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Allele, Càncer de pàncrees, Hepatocyte Nuclear Factor 1-beta, Cancer och onkologi, Biochemistry, Genetics and Molecular Biology (all), business.industry, Biochemistry, Genetics and Molecular Biology(all), Protein, Proteins, ADENOCARCINOMA, General Chemistry, Repressor Protein, medicine.disease, Pancreatic Neoplasms, Repressor Proteins, BODY-MASS INDEX, 030104 developmental biology, Tensin, Cancer and Oncology, Expression quantitative trait loci, lcsh:Q, business, ASSOCIATION ANALYSES, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10−8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10−14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10−10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10−8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10−8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene., Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

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