Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas.
Transforming growth factor beta (TGF-beta) is an extracellular ligand that binds to a heterodimeric receptor, initiating signals that regulate growth, differentiation, and apoptosis. Many cancers, including pancreatic cancer, harbor defects in TGF-beta signaling and are resistant to TGF-beta-mediated growth suppression. Genetic alterations of DPC4, which encodes a DNA binding protein that is a downstream component of the pathway, most frequently occur in pancreatic and biliary carcinomas. We searched for other targets of mutation of the TGF-beta pathway in these cancers. We report somatic alterations of the TGF-beta type I receptor gene ALK-5. Homozygous deletions of ALK-5 were identified in 1 of 97 pancreatic and 1 of 12 biliary adenocarcinomas. A germ-line variant of ALK-5, presumably a polymorphism, was identified, but no somatic intragenic mutations were identified upon sequencing of all coding regions of ALK-5. Somatic alterations of the TGF-beta type II receptor gene (TGFBR2) were identified in 4 of 97 (4.1%) pancreas cancers, including a homozygous deletion in a replication error-negative cancer and three homozygous frameshift mutations of the poly(A) tract of the TGF-beta type II receptor in replication error-positive cancers. We also studied other related type I receptors of the TGF-beta superfamily. In a panel of pancreas cancers preselected for loss of heterozygosity at the ALK-1 locus, sequencing of all coding exons of the ALK-1 gene revealed no alterations. No homozygous deletions were detected in the ALK-1, ALK-2, ALK-3, or ALK-6 genes in a panel of 86 pancreatic cancer xenografts and 11 pancreatic cancer and 22 breast cancer cell lines. The rate of genetic inactivation of TGF-beta pathway members was determined in 45 pancreatic cancers. Eighty-two % of these pancreatic cancers had genetic inactivation of the DPC4, p15, ALK-5, or TGFBR2 genes. Our results indicate that the TGF-beta type I and type II receptor genes are selective targets of genetic inactivation in pancreatic and biliary cancers.
Goggins
M
M
Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Shekher
M
M
Turnacioglu
K
K
Yeo
C J
CJ
Hruban
R H
RH
Kern
S E
SE
D029404:Activin Receptors; D000230:Adenocarcinoma / Q000235:genetics* / Q000648:ultrastructure; D000368:Aged; D001661:Biliary Tract Neoplasms / Q000235:genetics* / Q000648:ultrastructure; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019942:Genes, p16; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D000077294:Receptor, Transforming Growth Factor-beta Type II