PMID- 15328194
OWN - NLM
STAT- MEDLINE
DCOM- 20050217
LR  - 20040825
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 10
IP  - 16
DP  - 2004 Aug 15
TI  - The contribution of genetic and epigenetic changes in granulosa cell tumors of 
      ovarian origin.
PG  - 5537-45
AB  - PURPOSE: Granulosa cell tumors (GCTs) are relatively rare and are subtypes of the 
      sex-cord stromal neoplasms. A better understanding of the molecular genetics 
      underlying various steps in malignant transformation is critical to success in 
      the battle against this disease. Changes in the status of methylation, known as 
      epigenetic alterations, are one of the most common molecular alterations in human 
      cancers, including GCTs. Chromosomal instability and microsatellite instability 
      (MSI) are common in these GCTs. We tested the hypothesis that C-->T transition 
      polymorphism in the promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) 
      and its altered expression are also associated with hypermethylation of the 
      genes. We also attempted to determine the relationship between MSI of ovarian 
      carcinoma and hMLH1 hypermethylation in these tumors. EXPERIMENTAL DESIGN: We 
      studied chromosome instability in 25 GCTs by detecting gross chromosome 
      rearrangements in cultured peripheral blood lymphocytes. MSI was assessed using 
      six microsatellite markers (BAT25, BAT26, D2S123, D5S346, D11S1318, and D17S250). 
      Using sensitive methylation-specific PCR, we searched for aberrant promoter 
      hypermethylation in a panel of genes including p16, BRCA1, RASSF1A, ER-alpha, 
      TMS1, TIMP3, Twist, GSTP1, AR, and hMLH1. Polymorphism in the DNMT3B gene was 
      assessed by the PCR-RFLP method, and DNMT3B expression was studied by reverse 
      transcription-PCR assay. RESULTS: Chromosome instability was indicated by 
      significantly higher frequencies of chromosome aberrations (6.24%; P < 0.001) 
      compared with controls (2.12%). The most frequently observed changes include 
      trisomy 14 and monosomy 22. MSI has been found in 19 of 25 tumors, and loss of 
      heterozygosity has been found in 9 of 25 tumors. Frequencies of methylation in 
      GCTs were 40% for p16 and ER-alpha; 36% for BRCA1 and RASSF1A; 28% for hMLH1; 24% 
      for TIMP3, Twist, and GSTP1; and 20% in TMS1 and AR. TT genotype was found only 
      in two cases; the remainder were either CC or CT type. There was no significant 
      alteration in the expression of DNMT3B in these patients. CONCLUSIONS: 
      Coexistence of chromosome instability, MSI, and hypermethylation suggests that 
      both genetic and epigenetic mechanisms may act in concert to inactivate the 
      above-mentioned genes in these GCTs. These mechanisms can be an early event in 
      the pathogenesis of these tumors, and it can be a critical step in the 
      tumorigenic process. All these events might play an important role in early 
      clinical diagnosis and in chemotherapeutic management and treatment of the 
      disease. Larger studies may lend further understanding to the etiology and 
      clinical behavior of these tumors.
FAU - Dhillon, Varinderpal S
AU  - Dhillon VS
AD  - Cytogenetics Laboratory, Department of Biosciences, Jamia Milia Islamia, New 
      Delhi, India. Varinderpal.Dhillon@csiro.au
FAU - Aslam, Mohammad
AU  - Aslam M
FAU - Husain, Syed Akhtar
AU  - Husain SA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
SB  - IM
MH  - *Chromosome Aberrations
MH  - DNA Methylation
MH  - Female
MH  - *Genes, Tumor Suppressor
MH  - Granulosa Cell Tumor/*genetics
MH  - Humans
MH  - Microsatellite Repeats/genetics
MH  - Ovarian Neoplasms/*genetics
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Genetic
MH  - Transcription, Genetic
EDAT- 2004/08/26 05:00
MHDA- 2005/02/18 09:00
CRDT- 2004/08/26 05:00
PHST- 2004/08/26 05:00 [pubmed]
PHST- 2005/02/18 09:00 [medline]
PHST- 2004/08/26 05:00 [entrez]
AID - 10/16/5537 [pii]
AID - 10.1158/1078-0432.CCR-04-0228 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2004 Aug 15;10(16):5537-45. doi: 10.1158/1078-0432.CCR-04-0228.