Prognostic Value of PLAGL1-Specific CpG Site Methylation in Soft-Tissue Sarcomas

Abstract

Soft tissue sarcomas (STS) are rare, complex tumors with a poor prognosis. The identification of new prognostic biomarkers is needed to improve patient management. Our aim was to determine the methylation status of the 118 CpG sites in the PLAGL1 tumor-suppressor gene P1 CpG island promoter and study the potential prognostic impact of PLAGL1 promoter methylation CpG sites in STS. Training cohorts constituted of 28 undifferentiated sarcomas (US) and 35 leiomyosarcomas (LMS) were studied. PLAGL1 mRNA expression was investigated by microarray analysis and validated by RT-qPCR. Pyrosequencing was used to analyze quantitative methylation of the PLAGL1 promoter. Associations between global promoter or specific CpG site methylation and mRNA expression were evaluated using Pearson’s product moment correlation coefficient. Cox univariate and multivariate proportional hazard models were used to assess the predictive power of CpG site methylation status. Sixteen CpG sites associated with PLAGL1 mRNA expression were identified in US and 6 in LMS. Statistical analyses revealed an association between CpG107 methylation status and both overall and metastasis-free survival in US, which was confirmed in a validation cohort of 37 US. The exhaustive study of P1 PLAGL1 promoter methylation identified a specific CpG site methylation correlated with mRNA expression, which was predictive for both metastasis-free and overall survival and may constitute the first US-specific biomarker. Such a biomarker may be relevant for identifying patients likely to derive greater benefit from treatment.

Quantitative survey of multiple CpGs from 5 genes identifies CpG methylation panel discriminating between high- and low-grade cervical intraepithelial neoplasia

“…Only select CpG units may be used as markers distinguishing CIN II/III from CIN I/normal samples (Figure 3 B). Consistent with our observation, other reports has demonstrated that aberrant DNA methylation of only specific CpGs within the CGI are responsible for the downregulation of gene expression [ 40 - 44 ], and more recently, a substantial number of studies reported a specific, single CpG can function as strong prognostic or predictive indicators in various cancers [ 28 , 45 - 47 ].…”

Role of DNA methylation in imprinting disorders: an updated review

“…Aberrant hypomethylation of ICR/P1 on the maternal allele results in overexpression of PLAGL1 and HYMAI, which accounts for about 20% of TNDM1 patients [51,53]. Moreover, recent studies have shown the association between the methylation status of PLAGL1 promoter on chromosome 6 and different types of cancer, e.g., ovarian cancer and soft-tissue sarcomas [108,109].…”

DNA methylation patterns–based subtype distinction and identification of soft tissue sarcoma prognosis

“…Meanwhile, aberrant DNA methylation has been regarded as one of the hallmarks of cancer tissues [35,36], alterations in DNA methylation also play a virtual role in the progression and development of STSs [20,21]. In addition, S. Peter Wu et all had confirmed that methylation-based classifier could be used to provide diagnostic assistance in bone sarcoma [18].…”

“…At present, as a promising molecular marker of STSs, abnormal DNA methylation appears in early detection, prognosis prediction, molecular classification [18,19]. Meanwhile, multiple biological studies have also clarified that a series of methylations in gene promoter sequences is correlated with the prognosis and progression of STSs patients [20][21][22]. Nevertheless, the prognostic value of these aberrantly methylation sites in STSs subtypes and the complex role of DNA methylation in distinct gene regions are still largely unclarified and require further validation in the prognostic role of DNA methylation in STSs.…”