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 = 4.88×10−15), 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.

Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews

“…Together these studies identified 16 common low risk pancreatic cancer susceptibility loci that reached the genome-wide significance threshold: 10 −7.3 (i.e. P<5×10 −8 ) (Supplementary Table 1) (24–28). …”

Racial Disparity in Gastrointestinal Cancer Risk

“…There is no data on differences in pancreatic cancer risk by race/ethnicity in these high-risk syndromes. GWAS studies have identified 16 chromosomal loci with significant associations with pancreatic cancer [42,43]. These studies have included only a modest number of Blacks [44,45]) limiting evaluation of associations in this high-risk population.…”

Inherited pancreatic cancer

“…Recently, an imputation analysis of the GWAS data in 5,107 cases and 8,845 controls from PanScan I–III had uncovered three new pancreatic cancer signals on chromosome 1q32.1 ( NR5A2 ), 8q24.21 ( MYC ), and 5p15.33 ( CLPTM1L-TERT ), all of which are independent from previously reported susceptibility variants 107 .…”

“…To identify common susceptibility variants, five pancreatic cancer GWAS have been conducted by the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case Control Consortium (PanC4) in populations of European ancestry, including PanScan I in 2009 103 , PanScan II in 2010 104 , PanScan III in 2014 105 , PanC4 in 2015 106 and a recent imputation analysis of GWAS data from PanScan I–III 107 . A total of 16 pancreatic cancer susceptibility loci located in 13 genomic regions have been discovered in European populations (Table 2).…”

“…A third independent risk locus located in the first intron of TERT gene (rs2853677) was discovered through a candidate gene analysis in 5,550 pancreatic cancer cases and 7,585 control subjects from PANDoRA (PANcreatic Disease ReseArch) consortium and PanScan 123 . Recently, imputation of PanScan I–III and replication in PANDoRA and PanC4 found a fourth risk locus for pancreatic cancer in this genomic region (rs35226131), which is located about 200bps upstream of the transcriptional start site of TERT 107 . The chromosome 5p15.33 region contains two plausible candidate genes: TERT , which encodes the catalytic subunit of telomerase reverse transcriptase and CLPTM1L , which encodes the cleft lip and palate-associated transmembrane 1 like protein.…”