Aberrant methylation is a main mechanism of tumor suppressor gene inactivation in
carcinogenesis. In this study, the methylation status of RASSF1A, p16, MLH1, MSH2 and
ERalpha was investigated in 84 primary
soft tissue sarcomas (STSs), including 22
liposarcomas, 18
malignant fibrous histiocytomas (MFHs), 18
leiomyosarcomas, 6
rhabdomyosarcomas, 6
neurogenic sarcomas and several other
sarcoma entities. RASSF1A hypermethylation was detected in 17 of 84 (20%) STSs; however, methylation was more frequent in
leiomyosarcomas (39%) compared to MFHs (6%; p < 0.015) and
liposarcomas (18%). The p16 CpG island was methylated in 22 out of 82 (27%) cases. In 7 out of 81 (9%) STS samples, the promoter of MLH1 was methylated and in
liposarcoma the methylation frequency was higher (14%). For MSH2, no hypermethylation was detected. Methylation of
ERalpha was detected in 48 of 63 (76%) STSs, but also in 4 of 8 (50%) normal tissue samples. Furthermore, we analyzed mutational activation of K-ras and BRAF. In 4 out of 84 (5%) of STSs, a substitution at
codon 599 of BRAF was found; however, no alteration of K-ras was detected. In an univariate Cox proportional-hazards regression model, we found that the risk of a
tumor-related death for STS patients with methylated RASSF1A was significantly increased (RR = 2.9; p = 0.037). In summary, our data indicate that inactivation of RASSF1A is a common event in STS, especially in
leiomyosarcoma. Thus, the methylation status of
cancer-related genes was distinct in different STS and methylation of RASSF1A promoter can serve as prognostic marker in STSs.