TY - JOUR
T1 - A Novel Secretin Receptor Splice Variant Potentially Useful for Early Diagnosis of Pancreatic Carcinoma
AU - Hayes, Gregory M.
AU - Carrigan, Patricia E.
AU - Dong, Maoqing
AU - Reubi, Jean Claude
AU - Miller, Laurence J.
N1 - Funding Information:
Supported by grants from the National Institutes of Health, DK46577 and CA102701 (Mayo Clinic Pancreatic Cancer SPORE), a postdoctoral fellowship from the Canary Foundation/American Cancer Society, and support from the Fiterman Foundation.
PY - 2007/9
Y1 - 2007/9
N2 - Background & Aims: Pancreatic and bile duct carcinomas represent highly aggressive malignancies that evolve from secretin receptor-rich ductular cells. With premessenger RNA splicing abnormalities common in cancer, we evaluated whether an abnormal secretin receptor spliceoform were present, characterized it, and developed a serum assay for it. Methods: Cancer cell lines and healthy and neoplastic tissue were studied by nested reverse-transcription polymerase chain reaction and sequencing. A promising spliceoform was isolated and characterized, and monoclonal antibodies were raised to 2 distinct regions. A dual antibody enzyme-linked immunosorbent assay was developed and applied to blinded serum samples from 26 patients with pancreatic carcinoma, 10 patients with chronic pancreatitis, and 14 controls. Results: Each of 9 pancreatic cancer specimens and no normal tissue expressed a secretin receptor variant with exons 3 and 4 deleted. This encoded a 111-residue peptide with its first 43 residues identical to wild-type receptor, but, subsequent to a shift in coding frame and early truncation, the next 68 residues were unique in the transcriptome/proteome. This nonfunctional soluble protein did not bind or signal in response to secretin and was secreted from transfected MiaPaCa-2 cells. Elevated serum levels of this variant were present in 69% of pancreatic cancer patients, 60% of chronic pancreatitis patients, and 1 of 14 controls. Conclusions: We identified a novel abnormal spliceoform of the secretin receptor in pancreatic and bile duct cancers and developed a dual antibody sandwich enzyme-linked immunosorbent assay to measure it in the circulation. Initial application of this assay in patients with pancreatic cancer and chronic pancreatitis was promising, but additional validation will be required to evaluate its clinical utility.
AB - Background & Aims: Pancreatic and bile duct carcinomas represent highly aggressive malignancies that evolve from secretin receptor-rich ductular cells. With premessenger RNA splicing abnormalities common in cancer, we evaluated whether an abnormal secretin receptor spliceoform were present, characterized it, and developed a serum assay for it. Methods: Cancer cell lines and healthy and neoplastic tissue were studied by nested reverse-transcription polymerase chain reaction and sequencing. A promising spliceoform was isolated and characterized, and monoclonal antibodies were raised to 2 distinct regions. A dual antibody enzyme-linked immunosorbent assay was developed and applied to blinded serum samples from 26 patients with pancreatic carcinoma, 10 patients with chronic pancreatitis, and 14 controls. Results: Each of 9 pancreatic cancer specimens and no normal tissue expressed a secretin receptor variant with exons 3 and 4 deleted. This encoded a 111-residue peptide with its first 43 residues identical to wild-type receptor, but, subsequent to a shift in coding frame and early truncation, the next 68 residues were unique in the transcriptome/proteome. This nonfunctional soluble protein did not bind or signal in response to secretin and was secreted from transfected MiaPaCa-2 cells. Elevated serum levels of this variant were present in 69% of pancreatic cancer patients, 60% of chronic pancreatitis patients, and 1 of 14 controls. Conclusions: We identified a novel abnormal spliceoform of the secretin receptor in pancreatic and bile duct cancers and developed a dual antibody sandwich enzyme-linked immunosorbent assay to measure it in the circulation. Initial application of this assay in patients with pancreatic cancer and chronic pancreatitis was promising, but additional validation will be required to evaluate its clinical utility.
UR - http://www.scopus.com/inward/record.url?scp=34548490689&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548490689&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.06.013
DO - 10.1053/j.gastro.2007.06.013
M3 - Article
C2 - 17678920
AN - SCOPUS:34548490689
SN - 0016-5085
VL - 133
SP - 853
EP - 861
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -