Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: Gain of 9Q34 is an early event in insulinomas

The malignant potential among endocrine pancreatic tumors (EPTs) varies gre atly and can frequently not be predicted using histopathological parameters , Thus, molecular markers that can predict the biological behavior of EPTs are required. In a previous comparative genomic hybridization study, we obs erved marked genetic differences between the various EPT subtypes and a cor relation between losses of 3p and 6 and gains of 14q and Xq and metastatic disease. To search for genetic alterations that play a role during early tu mor development, we have studied 38 small (greater than or equal to2 em) EP Ts, including 24 insulinomas and 10 nonfunctioning EPTs. Small EPTs are usu ally classified as clinically benign tumors in the absence of histological signs of malignancy. Using comparative genomic hybridization, we identified chromosomal aberrations in 27 EPTs (mean, 4.1), Interestingly, the number of gains differed strongly between nonfunctioning and functioning EPTs (3.4 versus 1.5, respectively; P = 0.0526), as did the number of aberrations in the benign (n = 30) and malignant (n = 8) tumors (3 versus 8.4, respective ly; P = 0.0022). In the insulinomas, 9q gain (common region of involvement: 9q34) was most common (50%) and in nonfunctioning EPTs, gain of 4p was mos t common (40%) Most frequent losses in insulinomas involved 1p (20.8%), 1q, 4q, 11q, Xq, and Y (all 16.7%) and in nonfunctioning EPTs, 6q.. Losses of 3pq and 6q and gains of 17pq and 20q proved to be strongly associated with malignant behavior in all of the small EPTs (P less than or equal to 0.0219 ), Our results demonstrate marked genetic differences between small functio ning and nonfunctioning EPTs, indicating that these subtypes evolve along d ifferent genetic pathways. In addition, our study endorses the importance o f chromosomes 3 and 6q losses to discriminate EPTs with a malignant behavio r from benign ones.