title: Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors.
abstract: Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm's utility in prospective clinical decision-making are warranted.
authors.affiliation: Department of Surgery, The University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242-1086, USA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Sherman
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Maxwell
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Carr
authors.forename: Donghong
authors.initials: D
authors.lastname: Wang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellizzi
authors.forename: M
authors.initials: M
authors.lastname: Sue O'Dorisio
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Dorisio
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D007421:Intestine, Small / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000556:secondary*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018004:Receptors, Bombesin / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000235:genetics; D018045:Receptors, Oxytocin / Q000235:genetics; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C515653:OPRK1 protein, human; C569600:OXTR protein, human; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D017473:Receptors, Opioid, kappa; D018045:Receptors, Oxytocin; C107120:bombesin receptor subtype 3; C029937:secretin receptor