title: DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients.
abstract: The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size > or =2 cm, Ki67 proliferative index > or =2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 non-insulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan-Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P< or =0.0004) and tumor-specific death (P< or =0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index > or =2% were reliable in predicting a poor tumor-free survival in non-insulinoma EPTs (P< or =0.0181, whereas CK19 expression was the most optimal predictor of tumor-specific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in non-insulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.
authors.affiliation: Department of Molecular Cell Biology (Box 17), Research Institute for Growth and Development (GROW), University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. y.jonkers@molceb.unimass.nl
authors.forename: Y M H
authors.initials: YM
authors.lastname: Jonkers
authors.forename: S M H
authors.initials: SM
authors.lastname: Claessen
authors.forename: A
authors.initials: A
authors.lastname: Perren
authors.forename: A M
authors.initials: AM
authors.lastname: Schmitt
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: W
authors.initials: W
authors.lastname: de Herder
authors.forename: R R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: A A J
authors.initials: AA
authors.lastname: Verhofstad
authors.forename: A R
authors.initials: AR
authors.lastname: Hermus
authors.forename: J A
authors.initials: JA
authors.lastname: Kummer
authors.forename: B
authors.initials: B
authors.lastname: Skogseid
authors.forename: M
authors.initials: M
authors.lastname: Volante
authors.forename: A C
authors.initials: AC
authors.lastname: Voogd
authors.forename: F C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: E J M
authors.initials: EJ
authors.lastname: Speel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability; D002877:Chromosomes, Human; D004273:DNA, Neoplasm / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D015408:Gastrinoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018628:Gene Dosage; D006801:Humans; D007340:Insulinoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012680:Sensitivity and Specificity; D016019:Survival Analysis
chemical_list: D004273:DNA, Neoplasm; D019394:Ki-67 Antigen