biostudies-literatureZhang MCancer Research UKNCATS NIH HHSMedical Research CouncilNational Institute for Health Research (NIHR)NCI NIH HHS66328-66343https://www.ebi.ac.uk/biostudies/studies/S-EPMC5340084biostudies-literatureUnknown7(41)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.OncotargetThree new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.PMC5340084G1000143P30 CA008748UM1 CA182913NF-SI-0512-10114MR/N003284/1UL1 TR00186316491P30 CA016359P50 CA062924UG1 CA189953UG1 CA189974G0401527U01 CA210171U10 CA03742914136R01 CA154823UM1 CA182883Gazouli MSesso HDNeale REStrobel OScelo GZhang MBerndt SIOberg ALTrichopoulos DLe Marchand LTjonneland AAndreotti GZeleniuch-Jacquotte ABracci PMBasso DJenab MMocci EBrais LPezzilli RZheng WArslan AAWolpin BMKey TJLandi MTObazee OBrenner HHu NTravis RCCanzian FBuring JKaaks RBeane-Freeman LTobias GSYu KGoggins MKhaw KTYu HSilverman DTBoutron-Ruault MCGallinger SThornquist MKupcinskas JMalats NWhite ECaporaso NEKamineni ARiboli EKogevinas MLandi SPanico SHautman CQuiros JRAlbanes DCavestro GMMalecka-Panas EWentzensen NDuell EJRisch HAStolzenberg-Solomon RSKooperberg CSoucek PGiovannucci ELHassan MPurdue MWactawski-Wende JHartge PElena JPeeters PHAbnet CCBueno-de-Mesquita HBBoggi URothman NVisvanathan KPeters UJacobs EJCotterchio MTavano FWang ZKlein EAChanock SJMilne RLSund MGoodman GELi DHoover RKulke MHIskierka-Jazdzewska EHelzlsouer KJAmundadottir LTKurtz RCGoodman PJKraft PChilds EJOlson SHCapurso GTaylor PRChung CCKolonel LNHunter DJFiglioli GJia JVashist YPorta MKrogh VMambrini AHoskins JGiles GGPetersen GMHaiman CACostello EGross MPatel AVShu XOMannisto SKlein APVodicka PBurdette LBijlsma MFCollins IScarpa AGaziano JMFuchs CCampa DfalseThree new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.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.2016-01-01T00:00:00Z2016 Oct2024-02-15T03:27:39.219Z2019-03-27T02:38:01ZS-EPMC53400842757953310.18632/oncotarget.11041