Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization

Abstract

The molecular pathogenesis as well as histogenesis of endocrine pancreatic tumors (EPTs) is not well understood, and the clinical behavior of EPTs is difficult to predict using current morphological criteria. Thus, more accurate markers of risk and better understanding of tumor initiation and progression are needed to allow a precise classification of EPTs. We have studied 44 benign and malignant EPTs by comparative genomic hybridization to correlate the overall number of genetic alterations with clinical and histopathological parameters and to identify chromosomal regions which might harbor genes involved in EPT pathogenesis and progression. Aberrations were found in 36 EPTs, and chromosomal losses (mean, 5.3) were slightly more frequent than gains (mean, 4. 6). The most frequent losses involved Y (45% of male EPTs), 6q (39%), 11q (36%), 3p, 3q, 11p (each 30%), 6p (27%), and 10q and Xq (each 25%), whereas most common gains included 7q (43%), 17q (41%), 5q and 14q (each 32%), 7p, 9q, 17p, 20q (each 27%), and 12q and Xp (each 25%). A correlation was found between the total number of genetic changes per tumor and both tumor size and disease stage. In particular, losses of 3p and 6 and gains of 14q and Xq were found to be associated with metastatic disease. Furthermore, characteristic patterns of genetic changes were found in the various EPT subtypes, eg, 6q loss in malignant insulinomas, indicating that these groups might evolve along genetically different pathways. The highlighted genetic aberrations, including the newly found involvement of 6q losses and sex chromosome alterations, should stimulate the further analysis of these chromosomal regions, which may lead to the discovery of novel genes important in the tumorigenesis and evolution of EPTs.

Figure 1.

Summary of all DNA copy number changes detected by CGH in all 44 EPTs (A), 9 nonfunctioning EPTs (B), and 35 functioning EPTs (C). The vertical lines on the right of the chromosome ideograms indicate gains of the corresponding chromosomal regions; those on the left indicate losses. Gains on 1p, 16p, 19, and 22 were not analyzed.

Figure 2.

A: Representative CGH results in EPTs. Individual examples of fluorescent ratio profiles (right) and digital images (left) of chromosomes with recurrent gains and losses. The red vertical bar on the left side of a chromosome ideogram (middle) indicates the region of loss and the green vertical bar on the right side of an ideogram indicates the region of gain. B: Example of microsatellite and FISH LOH analysis of a nonfunctioning EPT shows allelic loss for 2 of 3 markers (D3S1029 and D3S1076, red arrowheads; D3S1110 is not informative) on chromosome arm 3p (left) and monosomy for both the centromere 3 (red spots) and 3p25-specific probe (green spots) in DAPI-stained tumor nuclei (right). C: Example of in situ hybridization analysis on paraffin sections of a male VIPoma sample, showing the expected one copy of the X centromere per nucleus in the major cell population (left) and a loss of the chromosome Y centromere sequence in the tumor cells, whereas the stroma cells in between (arrowheads) are still positive for this DNA sequence (right).