title: Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas.
abstract: BACKGROUND
  Dopamine 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.
  
  
  METHODS
  The exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  PRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas.
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. huagao@aliyun.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui Province, China. flyingsnowwf@126.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. 834054661@qq.com.|Neurosurgical Department, The Affiliated Hospital of Medical College, Qingdao University, China; and Capital Medical University, Beijing, China. 834054661@qq.com.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Lan
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. lichuzhong@163.com.
authors.forename: Chuzhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. fj79330@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Feng
authors.affiliation: Neurosurgical Department of Beijing Tiantan Hospital, Beijing, China. bai-12@163.com.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Bai
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. caolei_163@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Neurosurgical Department of Beijing Tiantan Hospital, Beijing, China. guisongbai@hotmail.com.
authors.forename: Songbai
authors.initials: S
authors.lastname: Gui
authors.affiliation: Tsinghua University, Beijing, China. homerhong1017@163.com.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Hong
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. zyz2004520@yeah.net.
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015175:Prolactinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D009687:Nuclear Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human; D004298:Dopamine