c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: incidence, mechanisms, and clinical significance.
Amplification and overexpression of c-MYC is a common event in various neoplasias. Recently, comparative genomic hybridization (CGH) of primary pancreatic adenocarcinomas revealed a distinct high-level amplification of 8q23-qter, suggesting that c-MYC located on 8q24 may be a candidate oncogene. To evaluate the biological significance and prognostic value of c-MYC activation in pancreatic carcinoma, we performed interphase fluorescence in situ hybridization (FISH) and immunohistochemistry on a series of 69 primary pancreatic adenocarcinomas, 19 corresponding lymph node metastases, and 5 pancreatic intraductal lesions. Dual color FISH using a probe for c-MYC (8q24) and a centromeric probe for chromosome 8 revealed amplification of c-MYC in 32.3% and 29.4% of primary and metastatic tumors, respectively. Immunostaining identified c-MYC protein overexpression in 43.5% of primaries and 31.6% of metastases. Low concordance between positive FISH and immunostaining (13.4%) suggests multiple independent regulatory pathways of c-MYC activation. Statistical evaluation revealed significant correlation (alpha = 0.033) between c-MYC protein overexpression and histopathological tumor grade but absence of correlation with tumor stage or lymph node status. Analysis of pancreatic intraductal lesions showed c-MYC amplification and protein overexpression in two of five cases in which invasive carcinoma exhibited identical aberrations. We conclude that deregulation of c-MYC protein is common in pancreatic cancer and that it may be involved in early neoplastic development and progression rather than in locoregional spread of invasive cancer.
Schleger
C
C
Institute of Pathology, Universitätsklinikum Mannheim, Germany. christiane.schleger@path.ma.uni-heidelberg.de
Verbeke
C
C
Hildenbrand
R
R
Zentgraf
H
H
Bleyl
U
U
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003627:Data Interpretation, Statistical; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*
D016271:Proto-Oncogene Proteins c-myc