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

Mingfeng Zhang, Zhaoming Wang, Ofure Obazee, Jinping Jia, Erica J. Childs, Jason Hoskins, Gisella Figlioli, Evelina Mocci, Irene Collins, Charles C. Chung, Christopher Hautman, Alan A. Arslan, Laura E. Beane-Freeman, Paige M. Bracci, Julie Buring, E. J. Duell, Steven Gallinger, Graham G. Giles, Gary Goodman, Phyllis J. Goodman & 103 others Aruna Kamineni, Laurence N. Kolonel, Matthew H. Kulke, N. Malats, Sara H. Olson, Howard D. Sesso, Kala Visvanathan, E. White, Wei Zheng, Christian C. Abnet, Demetrius Albanes, Gabriella Andreotti, Lauren Brais, H. Bas Bueno-De-Mesquita, Daniela Basso, Sonja I. Berndt, Marie Christine Boutron-Ruault, Maarten Bijlsma, Hermann Brenner, Laurie Burdette, Daniele Campa, Neil E. Caporaso, Gabriele Capurso, Giulia Martina Cavestro, Michelle Cotterchio, Eithne Costello, Joanne W. Elena, Ugo Boggi, J. Michael Gaziano, Maria Gazouli, Edward Giovannucci, Michael Goggins, Myron Gross, Christopher A. Haiman, Manal Hassan, Kathy Helzlsouer, Nan Hu, David J. Hunter, Elzbieta Iskierka-Jazdzewska, M. Jenab, Rudolf Kaaks, Timothy J. Key, Kay Thee Khaw, Eric A. Klein, Manolis Kogevinas, Vittorio Krogh, Juozas Kupcinskas, Robert C. Kurtz, Maria Teresa Landi, Stefano Landi, Loic Le Marchand, Andrea Mambrini, Satu Männistö, Roger L. Milne, Rachel E. Neale, Ann L. Oberg, S. Panico, Alpa V. Patel, P. H M Peeters, Ulrike Peters, Raffaele Pezzilli, Miquel Porta, Mark P. Purdue, J. Ram̊on Quir̊os, E. Riboli, Nathaniel Rothman, Aldo Scarpa, Ghislaine Scelo, Xiao Ou Shu, Debra T. Silverman, Pavel Souček, Oliver Strobel, M. Sund, Ewa Malecka-Panas, Philip R. Taylor, Francesca Tavano, Ruth C. Travis, M. D. Thornquist, A. Tjønneland, Geoffrey S. Tobias, Dimitrios Trichopoulos, Yogesh K. Vashist, Pavel Vodicka, Jean Wactawski-Wende, Nicolas Wentzensen, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Charles Kooperberg, Harvey A. Risch, E. J. Jacobs, Donghui Li, Charles S. Fuchs, Robert N. Hoover, Patricia Hartge, Stephen J. Chanock, Gloria M. Petersen, Rachael S. Stolzenberg-Solomon, Brian M. Wolpin, Peter Kraft, Alison P. Klein, F. Canzian, Laufey Amundadottir

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)66328-66343
Number of pages16
JournalOncotarget
Volume7
Issue number41
DOIs
Publication statusPublished - 2016

Fingerprint

Pancreatic Neoplasms
Chromosomes
Genome-Wide Association Study
Odds Ratio
Single Nucleotide Polymorphism
Neoplasms
Pancreatic Diseases
Case-Control Studies
Protein Isoforms
Alleles
Genome
Gene Expression
Research
Genes

Keywords

  • Fine-mapping
  • GWAS
  • Imputation
  • NR5A2
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Zhang, M., Wang, Z., Obazee, O., Jia, J., Childs, E. J., Hoskins, J., ... Amundadottir, L. (2016). Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget, 7(41), 66328-66343. https://doi.org/10.18632/oncotarget.11041

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. / 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 E.; Bracci, Paige M.; Buring, Julie; Duell, E. J.; Gallinger, Steven; Giles, Graham G.; Goodman, Gary; Goodman, Phyllis J.; Kamineni, Aruna; Kolonel, Laurence N.; Kulke, Matthew H.; Malats, N.; Olson, Sara H.; Sesso, Howard D.; Visvanathan, Kala; White, E.; Zheng, Wei; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Brais, Lauren; Bas Bueno-De-Mesquita, H.; Basso, Daniela; Berndt, Sonja I.; Boutron-Ruault, Marie Christine; Bijlsma, Maarten; Brenner, Hermann; Burdette, Laurie; Campa, Daniele; Caporaso, Neil E.; Capurso, Gabriele; Cavestro, Giulia Martina; Cotterchio, Michelle; Costello, Eithne; Elena, Joanne W.; Boggi, Ugo; Michael Gaziano, J.; Gazouli, Maria; Giovannucci, Edward; Goggins, Michael; Gross, Myron; Haiman, Christopher A.; Hassan, Manal; Helzlsouer, Kathy; Hu, Nan; Hunter, David J.; Iskierka-Jazdzewska, Elzbieta; Jenab, M.; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay Thee; Klein, Eric A.; Kogevinas, Manolis; Krogh, Vittorio; Kupcinskas, Juozas; Kurtz, Robert C.; Landi, Maria Teresa; Landi, Stefano; Marchand, Loic Le; Mambrini, Andrea; Männistö, Satu; Milne, Roger L.; Neale, Rachel E.; Oberg, Ann L.; Panico, S.; Patel, Alpa V.; Peeters, P. H M; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Purdue, Mark P.; Ram̊on Quir̊os, J.; Riboli, E.; Rothman, Nathaniel; Scarpa, Aldo; Scelo, Ghislaine; Shu, Xiao Ou; Silverman, Debra T.; Souček, Pavel; Strobel, Oliver; Sund, M.; Malecka-Panas, Ewa; Taylor, Philip R.; Tavano, Francesca; Travis, Ruth C.; Thornquist, M. D.; Tjønneland, A.; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Vashist, Yogesh K.; Vodicka, Pavel; Wactawski-Wende, Jean; Wentzensen, Nicolas; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Kooperberg, Charles; Risch, Harvey A.; Jacobs, E. J.; Li, Donghui; Fuchs, Charles S.; Hoover, Robert N.; Hartge, Patricia; Chanock, Stephen J.; Petersen, Gloria M.; Stolzenberg-Solomon, Rachael S.; Wolpin, Brian M.; Kraft, Peter; Klein, Alison P.; Canzian, F.; Amundadottir, Laufey.

In: Oncotarget, Vol. 7, No. 41, 2016, p. 66328-66343.

Research output: Contribution to journalArticle

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, LE, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, G, 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, Bas Bueno-De-Mesquita, H, Basso, D, Berndt, SI, Boutron-Ruault, MC, Bijlsma, M, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, JW, Boggi, U, Michael Gaziano, J, Gazouli, M, Giovannucci, E, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, K, 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, Marchand, LL, Mambrini, A, Männistö, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, MP, Ram̊on Quir̊os, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, XO, Silverman, DT, Souček, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, MD, Tjønneland, A, Tobias, GS, Trichopoulos, D, Vashist, YK, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, CS, Hoover, RN, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F & Amundadottir, L 2016, 'Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21', Oncotarget, vol. 7, no. 41, pp. 66328-66343. https://doi.org/10.18632/oncotarget.11041
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 E. ; Bracci, Paige M. ; Buring, Julie ; Duell, E. J. ; Gallinger, Steven ; Giles, Graham G. ; Goodman, Gary ; Goodman, Phyllis J. ; Kamineni, Aruna ; Kolonel, Laurence N. ; Kulke, Matthew H. ; Malats, N. ; Olson, Sara H. ; Sesso, Howard D. ; Visvanathan, Kala ; White, E. ; Zheng, Wei ; Abnet, Christian C. ; Albanes, Demetrius ; Andreotti, Gabriella ; Brais, Lauren ; Bas Bueno-De-Mesquita, H. ; Basso, Daniela ; Berndt, Sonja I. ; Boutron-Ruault, Marie Christine ; Bijlsma, Maarten ; Brenner, Hermann ; Burdette, Laurie ; Campa, Daniele ; Caporaso, Neil E. ; Capurso, Gabriele ; Cavestro, Giulia Martina ; Cotterchio, Michelle ; Costello, Eithne ; Elena, Joanne W. ; Boggi, Ugo ; Michael Gaziano, J. ; Gazouli, Maria ; Giovannucci, Edward ; Goggins, Michael ; Gross, Myron ; Haiman, Christopher A. ; Hassan, Manal ; Helzlsouer, Kathy ; Hu, Nan ; Hunter, David J. ; Iskierka-Jazdzewska, Elzbieta ; Jenab, M. ; Kaaks, Rudolf ; Key, Timothy J. ; Khaw, Kay Thee ; Klein, Eric A. ; Kogevinas, Manolis ; Krogh, Vittorio ; Kupcinskas, Juozas ; Kurtz, Robert C. ; Landi, Maria Teresa ; Landi, Stefano ; Marchand, Loic Le ; Mambrini, Andrea ; Männistö, Satu ; Milne, Roger L. ; Neale, Rachel E. ; Oberg, Ann L. ; Panico, S. ; Patel, Alpa V. ; Peeters, P. H M ; Peters, Ulrike ; Pezzilli, Raffaele ; Porta, Miquel ; Purdue, Mark P. ; Ram̊on Quir̊os, J. ; Riboli, E. ; Rothman, Nathaniel ; Scarpa, Aldo ; Scelo, Ghislaine ; Shu, Xiao Ou ; Silverman, Debra T. ; Souček, Pavel ; Strobel, Oliver ; Sund, M. ; Malecka-Panas, Ewa ; Taylor, Philip R. ; Tavano, Francesca ; Travis, Ruth C. ; Thornquist, M. D. ; Tjønneland, A. ; Tobias, Geoffrey S. ; Trichopoulos, Dimitrios ; Vashist, Yogesh K. ; Vodicka, Pavel ; Wactawski-Wende, Jean ; Wentzensen, Nicolas ; Yu, Herbert ; Yu, Kai ; Zeleniuch-Jacquotte, Anne ; Kooperberg, Charles ; Risch, Harvey A. ; Jacobs, E. J. ; Li, Donghui ; Fuchs, Charles S. ; Hoover, Robert N. ; Hartge, Patricia ; Chanock, Stephen J. ; Petersen, Gloria M. ; Stolzenberg-Solomon, Rachael S. ; Wolpin, Brian M. ; Kraft, Peter ; Klein, Alison P. ; Canzian, F. ; Amundadottir, Laufey. / Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. In: Oncotarget. 2016 ; Vol. 7, No. 41. pp. 66328-66343.
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title = "Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21",
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.",
keywords = "Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer",
author = "Mingfeng Zhang and Zhaoming Wang and Ofure Obazee and Jinping Jia and Childs, {Erica J.} and Jason Hoskins and Gisella Figlioli and Evelina Mocci and Irene Collins and Chung, {Charles C.} and Christopher Hautman and Arslan, {Alan A.} and Beane-Freeman, {Laura E.} and Bracci, {Paige M.} and Julie Buring and Duell, {E. J.} and Steven Gallinger and Giles, {Graham G.} and Gary Goodman and Goodman, {Phyllis J.} and Aruna Kamineni and Kolonel, {Laurence N.} and Kulke, {Matthew H.} and N. Malats and Olson, {Sara H.} and Sesso, {Howard D.} and Kala Visvanathan and E. White and Wei Zheng and Abnet, {Christian C.} and Demetrius Albanes and Gabriella Andreotti and Lauren Brais and {Bas Bueno-De-Mesquita}, H. and Daniela Basso and Berndt, {Sonja I.} and Boutron-Ruault, {Marie Christine} and Maarten Bijlsma and Hermann Brenner and Laurie Burdette and Daniele Campa and Caporaso, {Neil E.} and Gabriele Capurso and Cavestro, {Giulia Martina} and Michelle Cotterchio and Eithne Costello and Elena, {Joanne W.} and Ugo Boggi and {Michael Gaziano}, J. and Maria Gazouli and Edward Giovannucci and Michael Goggins and Myron Gross and Haiman, {Christopher A.} and Manal Hassan and Kathy Helzlsouer and Nan Hu and Hunter, {David J.} and Elzbieta Iskierka-Jazdzewska and M. Jenab and Rudolf Kaaks and Key, {Timothy J.} and Khaw, {Kay Thee} and Klein, {Eric A.} and Manolis Kogevinas and Vittorio Krogh and Juozas Kupcinskas and Kurtz, {Robert C.} and Landi, {Maria Teresa} and Stefano Landi and Marchand, {Loic Le} and Andrea Mambrini and Satu M{\"a}nnist{\"o} and Milne, {Roger L.} and Neale, {Rachel E.} and Oberg, {Ann L.} and S. Panico and Patel, {Alpa V.} and Peeters, {P. H M} and Ulrike Peters and Raffaele Pezzilli and Miquel Porta and Purdue, {Mark P.} and {Ram̊on Quir̊os}, J. and E. Riboli and Nathaniel Rothman and Aldo Scarpa and Ghislaine Scelo and Shu, {Xiao Ou} and Silverman, {Debra T.} and Pavel Souček and Oliver Strobel and M. Sund and Ewa Malecka-Panas and Taylor, {Philip R.} and Francesca Tavano and Travis, {Ruth C.} and Thornquist, {M. D.} and A. Tj{\o}nneland and Tobias, {Geoffrey S.} and Dimitrios Trichopoulos and Vashist, {Yogesh K.} and Pavel Vodicka and Jean Wactawski-Wende and Nicolas Wentzensen and Herbert Yu and Kai Yu and Anne Zeleniuch-Jacquotte and Charles Kooperberg and Risch, {Harvey A.} and Jacobs, {E. J.} and Donghui Li and Fuchs, {Charles S.} and Hoover, {Robert N.} and Patricia Hartge and Chanock, {Stephen J.} and Petersen, {Gloria M.} and Stolzenberg-Solomon, {Rachael S.} and Wolpin, {Brian M.} and Peter Kraft and Klein, {Alison P.} and F. Canzian and Laufey Amundadottir",
year = "2016",
doi = "10.18632/oncotarget.11041",
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volume = "7",
pages = "66328--66343",
journal = "Oncotarget",
issn = "1949-2553",
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TY - JOUR

T1 - Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

AU - Zhang, Mingfeng

AU - Wang, Zhaoming

AU - Obazee, Ofure

AU - Jia, Jinping

AU - Childs, Erica J.

AU - Hoskins, Jason

AU - Figlioli, Gisella

AU - Mocci, Evelina

AU - Collins, Irene

AU - Chung, Charles C.

AU - Hautman, Christopher

AU - Arslan, Alan A.

AU - Beane-Freeman, Laura E.

AU - Bracci, Paige M.

AU - Buring, Julie

AU - Duell, E. J.

AU - Gallinger, Steven

AU - Giles, Graham G.

AU - Goodman, Gary

AU - Goodman, Phyllis J.

AU - Kamineni, Aruna

AU - Kolonel, Laurence N.

AU - Kulke, Matthew H.

AU - Malats, N.

AU - Olson, Sara H.

AU - Sesso, Howard D.

AU - Visvanathan, Kala

AU - White, E.

AU - Zheng, Wei

AU - Abnet, Christian C.

AU - Albanes, Demetrius

AU - Andreotti, Gabriella

AU - Brais, Lauren

AU - Bas Bueno-De-Mesquita, H.

AU - Basso, Daniela

AU - Berndt, Sonja I.

AU - Boutron-Ruault, Marie Christine

AU - Bijlsma, Maarten

AU - Brenner, Hermann

AU - Burdette, Laurie

AU - Campa, Daniele

AU - Caporaso, Neil E.

AU - Capurso, Gabriele

AU - Cavestro, Giulia Martina

AU - Cotterchio, Michelle

AU - Costello, Eithne

AU - Elena, Joanne W.

AU - Boggi, Ugo

AU - Michael Gaziano, J.

AU - Gazouli, Maria

AU - Giovannucci, Edward

AU - Goggins, Michael

AU - Gross, Myron

AU - Haiman, Christopher A.

AU - Hassan, Manal

AU - Helzlsouer, Kathy

AU - Hu, Nan

AU - Hunter, David J.

AU - Iskierka-Jazdzewska, Elzbieta

AU - Jenab, M.

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Khaw, Kay Thee

AU - Klein, Eric A.

AU - Kogevinas, Manolis

AU - Krogh, Vittorio

AU - Kupcinskas, Juozas

AU - Kurtz, Robert C.

AU - Landi, Maria Teresa

AU - Landi, Stefano

AU - Marchand, Loic Le

AU - Mambrini, Andrea

AU - Männistö, Satu

AU - Milne, Roger L.

AU - Neale, Rachel E.

AU - Oberg, Ann L.

AU - Panico, S.

AU - Patel, Alpa V.

AU - Peeters, P. H M

AU - Peters, Ulrike

AU - Pezzilli, Raffaele

AU - Porta, Miquel

AU - Purdue, Mark P.

AU - Ram̊on Quir̊os, J.

AU - Riboli, E.

AU - Rothman, Nathaniel

AU - Scarpa, Aldo

AU - Scelo, Ghislaine

AU - Shu, Xiao Ou

AU - Silverman, Debra T.

AU - Souček, Pavel

AU - Strobel, Oliver

AU - Sund, M.

AU - Malecka-Panas, Ewa

AU - Taylor, Philip R.

AU - Tavano, Francesca

AU - Travis, Ruth C.

AU - Thornquist, M. D.

AU - Tjønneland, A.

AU - Tobias, Geoffrey S.

AU - Trichopoulos, Dimitrios

AU - Vashist, Yogesh K.

AU - Vodicka, Pavel

AU - Wactawski-Wende, Jean

AU - Wentzensen, Nicolas

AU - Yu, Herbert

AU - Yu, Kai

AU - Zeleniuch-Jacquotte, Anne

AU - Kooperberg, Charles

AU - Risch, Harvey A.

AU - Jacobs, E. J.

AU - Li, Donghui

AU - Fuchs, Charles S.

AU - Hoover, Robert N.

AU - Hartge, Patricia

AU - Chanock, Stephen J.

AU - Petersen, Gloria M.

AU - Stolzenberg-Solomon, Rachael S.

AU - Wolpin, Brian M.

AU - Kraft, Peter

AU - Klein, Alison P.

AU - Canzian, F.

AU - Amundadottir, Laufey

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Fine-mapping

KW - GWAS

KW - Imputation

KW - NR5A2

KW - Pancreatic cancer

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