Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal isletcells

The pathogenesis of sporadic endocrine pancreatic tumors (EPTs) is still pr imarily unknown, Comparative genomic hybridization studies revealed loss of 10q In a significant number (nine of 31) of EPTs, The tumor suppressor gen e PTEN lies on 10q23, and so, is a candidate to play some role in EPT patho genesis. Germline PTEN mutations are found in Cowden and Bannayan-Riley-Ruv alcaba syndromes, whereas somatic mutations and deletions are found in a va riety of sporadic cancers. The mutation and expression status of PTEN in EP Ts has not yet been examined. Mutation analysis of the entire coding region of PTEN including splice sites was performed in 33 tumors, revealing one t umor with somatic L182F (exon 6), Loss of heterozygosity of the 10q23 regio n was detected in eight of 15 informative malignant (53%) and in none of se ven benign EPTs, PTEN expression was assessed in 24 available EPTs by immun ohistochemistry using a monoclonal anti-PTEN antibody. Of these 24, 23 tumo rs showed strong immunoreactivity for PTEN, Only, the EPTs with PTEN mutati on lacked PTEN protein expression. Although normal islet cells always exhib ited predominantly nuclear PTEN immunostaining, 19 of 23 EPTs had a predomi nantly cytoplasmic PTEN expression pattern. Exocrine pancreatic tissue was PTEN-negative throughout. PTEN mutation is a rare event in malignant EPTs a nd PTEN protein is expressed in most (23 of 24) EPTs, Thus, intragenic muta tion or another means of physical loss of PTEN is rarely involved in the pa thogenesis of EPTs, Instead, either an impaired transport system of PTEN to the nucleus or some other means of differential compartmentalization could account for impaired PTEN function. Loss of heterozygosity of the 10q23 re gion is a frequent event in malignant EPTs and might suggest several hypoth eses: a different tumor suppressor gene in the vicinity of PTEN might be pr incipally involved in EPT formation; alternatively, 10q loss, including PTE N, seems to be associated with malignant transformation, but the first step toward neoplasia might involve altered subcellular localization of PTEN.