Abstract
Although family history is a risk factor for pancreatic adenocarcinoma, much of the genetic etiology of this disease remains unknown. While genome-wide association studies have identified some common single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk, these SNPs do not explain all the heritability of this disease. We hypothesized that copy number variation (CNVs) in the genome may play a role in genetic predisposition to pancreatic adenocarcinoma. Here, we report a genome-wide analysis of CNVs in a small hospital-based, European ancestry cohort of pancreatic cancer cases and controls. Germline CNV discovery was performed using the Illumina Human CNV370 platform in 223 pancreatic cancer cases (both sporadic and familial) and 169 controls. Following stringent quality control, we asked if global CNV burden was a risk factor for pancreatic cancer. Finally, we performed in silico CNV genotyping and association testing to discover novel CNV risk loci. When we examined the global CNV burden, we found no strong evidence that CNV burden plays a role in pancreatic cancer risk either overall or specifically in individuals with a family history of the disease. Similarly, we saw no significant evidence that any particular CNV is associated with pancreatic cancer risk. Taken together, these data suggest that CNVs do not contribute substantially to the genetic etiology of pancreatic cancer, though the results are tempered by small sample size and large experimental variability inherent in array-based CNV studies.
Highlights
Pancreatic adenocarcinoma is the fourth-leading cause of cancer mortality in the United States for both men and women (Siegel et al, 2012)
Putative rare or de novo copy number variations (CNVs) burden To explore whether putative rare or de novo CNV burden is associated with pancreatic cancer risk, we extended the above analysis by considering only the subset of 377 CNV calls detected in a single individual in our study (Table 4)
In this study, we sought to investigate the roles of CNV burden and individual CNV loci in pancreatic cancer susceptibility
Summary
Pancreatic adenocarcinoma is the fourth-leading cause of cancer mortality in the United States for both men and women (Siegel et al, 2012). Inherited genetic predisposition to pancreatic cancer is hypothesized to play a role in both familial and non-familial forms of the disease. Additional studies have focused their analyses on SNPs within candidate genes (Jiao et al, 2006, 2008; Li et al, 2007; McWilliams et al, 2008). Under this approach, SNPs within DNA damage response and repair genes— ATM, LIG3, XRCC1, and XRCC2 genes—were associated with increased risk, suggesting the involvement of inherited genetic variants within these pathways in pancreatic tumorigenesis
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