Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells.
The pathogenesis of sporadic endocrine pancreatic tumors (EPTs) is still primarily unknown. Comparative genomic hybridization studies revealed loss of 10q in a significant number (nine of 31) of EPTs. The tumor suppressor gene PTEN lies on 10q23, and so, is a candidate to play some role in EPT pathogenesis. Germline PTEN mutations are found in Cowden and Bannayan-Riley-Ruvalcaba syndromes, whereas somatic mutations and deletions are found in a variety of sporadic cancers. The mutation and expression status of PTEN in EPTs has not yet been examined. Mutation analysis of the entire coding region of PTEN including splice sites was performed in 33 tumors, revealing one tumor with somatic L182F (exon 6). Loss of heterozygosity of the 10q23 region was detected in eight of 15 informative malignant (53%) and in none of seven benign EPTs. PTEN expression was assessed in 24 available EPTs by immunohistochemistry using a monoclonal anti-PTEN antibody. Of these 24, 23 tumors showed strong immunoreactivity for PTEN. Only the EPTs with PTEN mutation lacked PTEN protein expression. Although normal islet cells always exhibited predominantly nuclear PTEN immunostaining, 19 of 23 EPTs had a predominantly cytoplasmic PTEN expression pattern. Exocrine pancreatic tissue was PTEN-negative throughout. PTEN mutation is a rare event in malignant EPTs and PTEN protein is expressed in most (23 of 24) EPTs. Thus, intragenic mutation or another means of physical loss of PTEN is rarely involved in the pathogenesis 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 region is a frequent event in malignant EPTs and might suggest several hypotheses: a different tumor suppressor gene in the vicinity of PTEN might be principally involved in EPT formation; alternatively, 10q loss, including PTEN, seems to be associated with malignant transformation, but the first step toward neoplasia might involve altered subcellular localization of PTEN.
Perren
A
A
Department of Pathology, University of Zürich, Zurich, Switzerland.
Komminoth
P
P
Saremaslani
P
P
Matter
C
C
Feurer
S
S
Lees
J A
JA
Heitz
P U
PU
Eng
C
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005935:Glucagonoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D018807:Polymorphism, Single-Stranded Conformational; D012016:Reference Values; D013347:Subcellular Fractions / Q000378:metabolism*; D014018:Tissue Distribution; D025521:Tumor Suppressor Proteins
D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human