Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas

Abstract

BackgroundDopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients.MethodsThe exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing.ResultsUsing stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence.ConclusionsPRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1267-0) contains supplementary material, which is available to authorized users.

Combining Cadherin Expression with Molecular Markers Discriminates Invasiveness in Growth Hormone and Prolactin Pituitary Adenomas

“…To address this point, we chose a gene candidate approach by analysing cadherin expression in association with the pattern of expression of known molecular markers related to pituitary tumour behaviour and susceptibility to organise tumours. Of note, the number of genes used in binary tree analysis is not limited and the results of emerging studies of exome array analysis in pituitary adenomas (51,52) would allow an increase in the number of genes in future studies. Such strategies could be applied to invasive behaviour, resistance to dopamine agonists or somatostatin receptor analogues, and tumour recurrence.…”

Genome Evolution Analysis of Recurrent Testicular Malignant Mesothelioma by Whole-Genome Sequencing

“…PRDM2, a member of histone methyltransferase superfamily, is a candidate tumor suppressor and is closely related to several other critical oncogene and tumor suppressor, including RB1 and TP53 [19][20]. Reduced expression of PRDM2 was associated with drug resistance, tumor recurrence, and tumorigenesis in some cancers [20,21]. Consistently, a recent study using comprehensive genomic analysis recognized this gene with frequent mutations in MPM [22].…”

RIZ1 and histone methylation status in pituitary adenomas

“…According to a genetic perspective, RIZ1 may be downregulated by chromosomal instability and microsatellite instability, as well as frame-shift mutations, point mutations, and heterozygote deficiency. [25][26][27] From an epigenetic perspective, the deactivation of RIZ1 may occur due to promoter methylation and histone acetylation. The RIZ1 promoter has been demonstrated to have the characteristics of a CpG island, which suggests that RIZ1 is a target of inactivation by epigenetic mechanisms.…”