Authors: Jill P. Smith, John Harms, Gail L. Matters, Christopher O. McGovern, Francesca M. Ruggiero, Jiangang Liao, Kristin K. Fino, Emily E. Ortega, Evan L. Gilius and John A. Phillips III

Jill P. Smith

Corresponding author: jsmith2@psu.edu
Department of Medicine; Pennsylvania State University; Hershey, PA USA

John Harms

Department of Biological Sciences; Messiah College; Grantham, PA USA

Gail L. Matters

Department of Biochemistry and Molecular Biology; Pennsylvania State University; Hershey, PA USA

Christopher O. McGovern

Department of Medicine; Pennsylvania State University; Hershey, PA USA

Francesca M. Ruggiero

Department of Pathology; Pennsylvania State University; Hershey, PA USA

Jiangang Liao

Public Health Sciences; Pennsylvania State University; Hershey, PA USA

Kristin K. Fino

Department of Medicine; Pennsylvania State University; Hershey, PA USA

Emily E. Ortega

Department of Medicine; Pennsylvania State University; Hershey, PA USA

Evan L. Gilius

Department of Medicine; Pennsylvania State University; Hershey, PA USA

John A. Phillips III

Division of Medical Genetics and Genomic Medicine; Vanderbilt University School of Medicine; Nashville, TN USA

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Abstract:

There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.