A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer

Jill P. Smith, John F. Harms, Gail Matters, Christopher O. McGovern, Francesca Ruggiero, Jiangang (Jason) Liao, Kristin K. Fino, Emily E. Ortega, Evan L. Gilius, John A. Phillips

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12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)164-174
Number of pages11
JournalCancer Biology and Therapy
Volume13
Issue number3
DOIs
StatePublished - Feb 1 2012

Fingerprint

Cholecystokinin B Receptor
Pancreatic Neoplasms
Single Nucleotide Polymorphism
Genotype
Introns
Survival
Protein Isoforms
Genes
Genome-Wide Association Study
Gastrins
Genetic Testing
Adjuvant Chemotherapy
Early Detection of Cancer
Early Diagnosis
Pancreas
Adenocarcinoma
Lymph Nodes
Alleles
Antibodies
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Smith, Jill P. ; Harms, John F. ; Matters, Gail ; McGovern, Christopher O. ; Ruggiero, Francesca ; Liao, Jiangang (Jason) ; Fino, Kristin K. ; Ortega, Emily E. ; Gilius, Evan L. ; Phillips, John A. / A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer. In: Cancer Biology and Therapy. 2012 ; Vol. 13, No. 3. pp. 164-174.
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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.",
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A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer. / Smith, Jill P.; Harms, John F.; Matters, Gail; McGovern, Christopher O.; Ruggiero, Francesca; Liao, Jiangang (Jason); Fino, Kristin K.; Ortega, Emily E.; Gilius, Evan L.; Phillips, John A.

In: Cancer Biology and Therapy, Vol. 13, No. 3, 01.02.2012, p. 164-174.

Research output: Contribution to journalArticle

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AU - Harms, John F.

AU - Matters, Gail

AU - McGovern, Christopher O.

AU - Ruggiero, Francesca

AU - Liao, Jiangang (Jason)

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N2 - 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.

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