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

被引：87

作者：

Zhang, Mingfeng ^{[1
]}

Wang, Zhaoming ^{[2
,3
,103
]}

Obazee, Ofure ^{[4
]}

Jia, Jinping ^{[1
]}

Childs, Erica J. ^{[5
]}

Hoskins, Jason ^{[1
]}

Figlioli, Gisella ^{[4
]}

Mocci, Evelina ^{[5
]}

Collins, Irene ^{[1
]}

Chung, Charles C. ^{[2
,3
]}

Hautman, Christopher ^{[1
]}

Arslan, Alan A. ^{[6
,7
,8
]}

Beane-Freeman, Laura ^{[2
]}

Bracci, Paige M. ^{[9
]}

Buring, Julie ^{[10
,11
,12
]}

Duell, Eric J. ^{[13
]}

Gallinger, Steven ^{[14
]}

Giles, Graham G. ^{[15
,16
,17
]}

Goodman, Gary E. ^{[18
]}

Goodman, Phyllis J. ^{[19
]}

Kamineni, Aruna ^{[20
]}

Kolonel, Laurence N. ^{[21
]}

Kulke, Matthew H. ^{[22
]}

Malats, Nuria ^{[23
]}

Olson, Sara H. ^{[24
]}

Sesso, Howard D. ^{[10
,11
,12
,25
]}

Visvanathan, Kala ^{[26
]}

White, Emily ^{[18
,27
]}

Zheng, Wei ^{[28
,29
]}

Abnet, Christian C. ^{[2
]}

Albanes, Demetrius ^{[2
]}

Andreotti, Gabriella ^{[2
]}

Brais, Lauren ^{[22
]}

Bueno-de-Mesquita, H. Bas ^{[30
,31
,32
]}

Basso, Daniela ^{[33
]}

Berndt, Sonja I. ^{[2
]}

Boutron-Ruault, Marie-Christine ^{[34
,35
,36
]}

Bijlsma, Maarten F. ^{[37
]}

Brenner, Hermann ^{[38
,39
,40
,41
]}

Burdette, Laurie ^{[2
,3
]}

Campa, Daniele ^{[42
]}

Caporaso, Neil E. ^{[2
]}

Capurso, Gabriele ^{[43
]}

Cavestro, Giulia Martina ^{[44
]}

Cotterchio, Michelle ^{[45
,46
]}

Costello, Eithne ^{[47
]}

Elena, Joanne ^{[48
]}

Boggi, Ugo ^{[49
]}

Gaziano, J. Michael ^{[10
,11
,12
,50
]}

Gazouli, Maria ^{[51
]}

机构：

[1] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[2] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[3] Leidos Biomed Res Inc, Canc Genom Res Lab, NCI, Div Canc Epidemiol & Genet,Frederick Natl Lab Can, Frederick, MD USA

[4] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[6] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA

[7] NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA

[8] NYU, Inst Canc, New York, NY USA

[9] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[10] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA

[11] Harvard Med Sch, Boston, MA USA

[12] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA

[13] Catalan Inst Oncol ICO, Unit Nutr & Canc, Canc Epidemiol Res Program, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain

[14] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[15] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia

[16] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia

[17] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia

[18] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[19] Fred Hutchinson Canc Res Ctr, Ctr Stat, Southwest Oncol Grp, 1124 Columbia St, Seattle, WA 98104 USA

[20] Grp Hlth Res Inst, Seattle, WA USA

[21] Univ Hawaii, Canc Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA

[22] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[23] CNIO Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain

[24] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[25] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[26] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA

[27] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[28] Vanderbilt Univ, Div Epidemiol, Med Ctr, Nashville, TN USA

[29] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN USA

[30] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands

[31] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[32] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia

[33] Univ Hosp Padova, Dept Lab Med, Padua, Italy

[34] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, F-94805 Villejuif, France

[35] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France

[36] IGR, F-94805 Villejuif, France

[37] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, Amsterdam, Netherlands

[38] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[39] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[40] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[41] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[42] Univ Pisa, Dept Biol, Pisa, Italy

[43] Sapienza Univ Rome, Digest & Liver Dis Unit, Rome, Italy

[44] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Gastroenterol & Gastrointestinal Endoscopy Unit, Milan, Italy

[45] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada

[46] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada

[47] Univ Liverpool, Natl Inst Hlth Res Liverpool Pancreas Biomed Res, Liverpool, Merseyside, England

[48] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA

[49] Univ Hosp Pisa, Dept Surg, Unit Expt Surg Pathol, Pisa, Italy

[50] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Geriatr Res Educ & Clin Ctr, Boston, MA USA

来源：

ONCOTARGET | 2016年 / 7卷 / 41期

基金：

美国国家卫生研究院;

关键词：

pancreatic cancer; GWAS; fine-mapping; imputation; NR5A2; GENOME-WIDE ASSOCIATION; LONG-RANGE INTERACTION; RISK LOCI; GENOTYPE IMPUTATION; GENETIC SUSCEPTIBILITY; TERT-CLPTM1L LOCUS; BLADDER-CANCER; COMMON VARIANT; BREAST; LRH-1;

D O I：

10.18632/oncotarget.11041

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：66328 / 66343

页数：16

共 15 条

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