Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round-cell liposarcoma.
The adenomatous polyposis coli (APC) protein is a key component of the WNT signalling pathway wherein it acts as a scaffolding protein in controlling the level of the proto-oncoprotein beta-catenin. Although APC has been shown to be genetically or epigenetically inactivated in a variety of carcinomas, little is known about its role in sarcoma. Liposarcomas (LPSs) are the second most common soft tissue sarcoma in adults. Despite different histology and malignancy, the myxoid and round-cell LPSs belong to one tumour entity characterized by a specific chromosomal translocation. We assessed the extent of genetic and epigenetic inactivation of the APC gene in myxoid/round-cell LPS. Sequencing of the mutation cluster region, the protein truncation test and a loss of heterozygosity (LOH) analysis did not reveal any genetic alterations of the APC gene in all of the liposarcoma samples. Methylation of the APC promoter was detected by methylation-specific PCR in 9 of 20 (45%) tumours. Analysis of APC expression by semiquantitative RT-PCR in a subset of the samples demonstrated that tumours with a methylated APC promoter showed a downregulation of the APC transcript. However, APC downregulation was not correlated with a stabilisation of the beta-catenin protein. Thus, the epigenetic regulation of the APC gene might play an important role in the pathogenesis of myxoid/round-cell LPS. However, the impact of APC methylation on liposarcoma development is quite likely not mediated through WNT signalling.
Sievers
Sonja
S
Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. sonja.sievers@mpi-dortmund.mpg.de
Fritzsch
Carla
C
Lehnhardt
Marcus
M
Zahn
Susanne
S
Kutzner
Nadine
N
Kuhnen
Cornelius
C
Müller
Oliver
O
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D017491:Genes, APC; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000235:genetics* / Q000473:pathology*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D051176:beta Catenin / Q000032:analysis
C495270:CTNNB1 protein, human; D051176:beta Catenin