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A Meta-analysis and a cohort study indicate association between RASSF1A promoter methylation and testicular germ cell tumor

The RAS association domain family protein 1a (RASSF1A) is a prominent tumor suppressor similar to RAS effector proteins. It shows altered promoter methylation in many different cancer types including testicular germ cell tumors (TGCT). TGCT are the most common malignancy in young men and they account for approximately 1% of all human malignancies. RASSF1A promoter hypermethylation might represent an early event in TGCT tumorigenesis. In addition to epigenetic studies on tumor tissue, in the last decade, there have been several reports showing correlation between peripheral blood DNA methylation and tumor status. Given the fact that peripheral blood is easily accessible, it is clear that its DNA methylation analysis holds a promise in finding suitable cancer markers. We investigated whether the RASSF1A promoter methylation in peripheral blood of TGCT patients can be associated with testicular cancer risk. Following a meta-analysis, we performed a cohort study including 32 testicular cancer patients and 32 healthy controls. Promoter methylation of the RASSF1A and O6-methylguanine-DNA- methyltransferase (MGMT) genes was analyzed using bisulfite pyrosequencing of DNA from peripheral blood. Meta-analysis showed an odds ratio (OR) of 7.69 for RASSF1A promoter methylation as a risk factor for TGCT. Cohort study found altered methylation of the RASSF1A promoter in blood of TGCT patients. Methylation was higher in TGCT patients before BEP (bleomycin, etoposide, cisplatin) chemotherapy. The meta- analysis indicates a role of the RASSF1A promoter hypermethylation from peripheral blood in TGCT. We confirmed the findings of meta-analysis (encompassing mainly tumor tissue) in our cohort study, which represents the first report of changed RASSF1A promoter methylation in peripheral blood TGCT. We envision that further studies including larger number of patients will bring more light into the potential of using RASSF1A peripheral blood methylation status as a TGCT marker.

RASSF1a ; testicular cancer ; methylation ; meta analysis

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