Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.
BACKGROUND
Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32-34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene.


RESULTS
A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate.


CONCLUSIONS
These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.
Pogue-Geile
Kay L
KL
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Chen
Ru
R
Bronner
Mary P
MP
Crnogorac-Jurcevic
Tatjana
T
Moyes
Kara White
KW
Dowen
Sally
S
Otey
Carol A
CA
Crispin
David A
DA
George
Ryan D
RD
Whitcomb
David C
DC
Brentnall
Teresa A
TA
D000185:Actinin / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics*; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000235:genetics; D002465:Cell Movement; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D003599:Cytoskeleton / Q000502:physiology; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D014162:Transfection
D003598:Cytoskeletal Proteins; C412722:PALLD protein, human; D010750:Phosphoproteins; D000185:Actinin