TY - JOUR
T1 - A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer
AU - Smith, Jill P.
AU - Harms, John F.
AU - Matters, Gail L.
AU - McGovern, Christopher O.
AU - Ruggiero, Francesca M.
AU - Liao, Jiangang
AU - Fino, Kristin K.
AU - Ortega, Emily E.
AU - Gilius, Evan L.
AU - Phillips, John A.
N1 - Funding Information:
The research was supported by the National Institutes of Health, National Cancer Institute grant (R01 CA117926 to J.P.S.); and an American Cancer Society post-doctoral fellow-ship award (PF-04-104-01-CSM to J.F.H.) Additional funding was provided through an educational grant from the National Institutes of Health (R25 DK078381 to G.L.M.) for a student in the STEP-UP program. We acknowledge the technical assistance of David Stanford and Nate Shaeffer in the Cell Science Flow Cytometry Core, Joe Bednarczyk in the DNA Sequencing Core, and Rob Brucklacher and Georgina Bixler of the Functional Genomics Core of the Section of Research Resources. We appreciate the technical assistance of Calpurnia Jayakumar (Department of Medicine) and Richard Bruggeman (The Morphologic and Molecular Pathology Research Lab of the Department of Pathology) from the Pennsylvania State University College of Medicine for immunohistochemical stain-DisclosureofPotentialConflictsofInterest ing of tissue specimens. We acknowledge Daniel Beard from J.S., J.H. and G.M. have intellectual property and a provisional the Tumor Bank from the Penn State Cancer Institute
PY - 2012/2/1
Y1 - 2012/2/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863138653&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863138653&partnerID=8YFLogxK
U2 - 10.4161/cbt.13.3.18698
DO - 10.4161/cbt.13.3.18698
M3 - Article
C2 - 22277584
AN - SCOPUS:84863138653
SN - 1538-4047
VL - 13
SP - 164
EP - 174
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 3
ER -