Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer.
SMAD4 (DPC4) is part of the TGFB signaling pathway and is frequently inactivated in pancreatic carcinomas. TGFB signals from the membrane to the nucleus via SMAD proteins. TGFB receptor activation results in SMAD2 and SMAD3 phosphorylation, which then form heteromeric complexes with SMAD4. Inhibitory SMADs, SMAD6 and SMAD7, can prevent TGFB signaling by interacting either with the receptor or with SMAD2 and SMAD3. The encoding sequences for these proteins are organized in two gene clusters, one at 18q21 (SMAD2, SMAD4, and SMAD7) and the other at 15q21-22 (SMAD3 and SMAD6). Losses of 15q and 18q material are frequent in pancreatic carcinomas, and in order to map the extent of 15q and 18q deletions and to investigate further the involvement of SMAD4 and the possible function of SMAD2 and SMAD3 as tumor suppressor genes in pancreatic carcinoma, we performed loss of heterozygosity studies as well as mutation and expression analyses of SMAD4, SMAD2, and SMAD3 in 13 low-passage cell lines from 12 pancreatic carcinoma patients. To investigate possible amplifications of SMAD6 and SMAD7, the genomic organization and the expression levels of these genes were analyzed. One tumor with homozygous loss of SMAD4 was detected, and mutations of this gene were found in four of the 12 carcinomas; no SMAD2 or SMAD3 inactivating genomic alterations were found. In none of the cases was transcriptional silencing seen. No genomic amplifications, mutations, or increased expression of SMAD6 and SMAD7 were detected. These results suggest that functional abrogation of SMAD2 or SMAD3 and increased expression of SMAD6 or SMAD7 are infrequent in pancreatic carcinomas and further stress the particular importance of SMAD4 inactivation in pancreatic carcinogenesis.
Jonson
T
T
Department of Clinical Genetics, University Hospital, Lund, Sweden. Tord.Jonson@klingen.lu.se
Gorunova
L
L
Dawiskiba
S
S
Andrén-Sandberg
A
A
Stenman
G
G
ten Dijke
P
P
Johansson
B
B
Höglund
M
M
D000368:Aged; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators