carcinoma; DNA methylation; endometrium; RARb2; RASSF1A
Abstract :
[en] Aims: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis.
<br />Methods and results: Archival biopsy specimens of 39 EECs, 14 cases of atypical hyperplasia (AH), 11 histologically normal endometrial tissues adjacent to EECs and 24 normal control endometrial samples were retrieved. The cases were tested by quantitative methylation-specific polymerase chain reaction with primers hybridizing in the promoter regions of five genes frequently methylated in human cancer (RASSF1A, RARb2, P16, MGMT and GSTPi). Twenty-nine of 39 (74%) EECs and 7/14 (50%) AHs were methylated for the RASSF1A gene, whereas 17/39 (44%) EECs and 6/14 (43%) AHs were positive for the methylation of the RARb2 gene. No significant results were obtained for the other genes (P16, MGMT and GSTPi). Interestingly, 4/11 (36%) and 6/11 (55%) histologically normal endometrial tissues adjacent to EEC showed, respectively, RASSF1A and RARb2 gene methylation. Furthermore, these 11 specimens were microsatellite stable and showed similar proliferative, cell cycle and apoptotic mean labelling indices as the normal endometrial control tissues.
<br />Conclusions: Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis.
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement
Boniver, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Language :
English
Title :
High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarinoma
Emons G, Fleckenstein G, Hinney B, Huschmand A, Heyl W. Hormonal interactions in endometrial cancer. Endocr. Relat. Cancer. 2000 7 227 242.
Hecht JL, Mutter GL. Molecular and pathologic aspects of endometrial carcinogenesis. J. Clin. Oncol. 2006 24 4783 4791.
Matias-Guiu X, Catasus L, Bussaglia E et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum. Pathol. 2001 32 569 577.
McCluggage WG. My approach to the interpretation of endometrial biopsies and curettings. J. Clin. Pathol. 2006 59 801 812.
Esteller M. Dormant hypermethylated tumour suppressor genes: questions and answers. J. Pathol. 2005 205 172 180.
Li S, Hursting SD, Davis BJ, McLachlan JA, Barrett JC. Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann. NY Acad. Sci. 2003 983 161 169.
Belinsky SA, Nikula KJ, Palmisano WA et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Natl Acad. Sci. USA 1998 95 11891 11896.
Dhawan D, Hamdy FC, Rehman I et al. Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma. J. Pathol. 2006 209 336 343.
Lewis CM, Cler LR, Bu DW et al. Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. Clin. Cancer Res. 2005 11 166 172.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA. 1996 93 9821 9826.
Di Gioia S, Bianchi P, Destro A et al. Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver. BMC Cancer 2006 6 89.
Pizzi S, Azzoni C, Bottarelli L et al. RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J. Pathol. 2005 206 409 416.
Widschwendter M, Berger J, Hermann M et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J. Natl. Cancer Inst. 2000 92 826 832.
Youssef EM, Lotan D, Issa JP et al. Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin. Cancer Res. 2004 10 1733 1742.
Sun Y, Deng D, You WC et al. Methylation of p16 CpG islands associated with malignant transformation of gastric dysplasia in a population-based study. Clin. Cancer Res. 2004 10 5087 5093.
Vallbohmer D, Brabender J, Yang D et al. DNA methyltransferases messenger RNA expression and aberrant methylation of CpG islands in non-small-cell lung cancer: association and prognostic value. Clin. Lung Cancer. 2006 8 39 44.
Chan QK, Khoo US, Chan KY et al. Promoter methylation and differential expression of pi-class glutathione S-transferase in endometrial carcinoma. J. Mol. Diagn. 2005 7 8 16.
Jeronimo C, Henrique R, Hoque MO et al. A quantitative promoter methylation profile of prostate cancer. Clin. Cancer Res. 2004 10 8472 8478.
Umar A, Boland CR, Terdiman JP et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004 96 261 268.
Kang S, Kim JW, Kang GH et al. Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma. Int. J. Cancer 2006 118 2168 2171.
Li R, Saito T, Tanaka R et al. Hypermethylation in promoter region of retinoic acid receptor-beta gene and immunohistochemical findings on retinoic acid receptors in carcinogenesis of endometrium. Cancer Lett. 2005 219 33 40.
Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 2002 21 5380 5387.
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 2002 3 415 428.
Kim DH, Kim JS, Park JH et al. Relationship of Ras association domain family 1 methylation and K-ras mutation in primary non-small cell lung cancer. Cancer Res. 2003 63 6206 6211.
Slaughter DP, Southwick HW, Smejkal W. 'Field cancerisation' in oral stratified squamous epithelium. Cancer 1953 6 963 968.
Furlan D, Carnevali I, Marcomini B et al. The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas. Clin. Cancer Res. 2006 12 3329 3336.
Garcia SB, Park HS, Novelli M, Wright NA. Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J. Pathol. 1999 187 61 81.
Eads CA, Lord RV, Wickramasinghe K et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 2001 61 3410 3418.
Kang GH, Lee S, Lee HJ, Hwang KS. Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. J. Pathol. 2004 202 233 240.
Kanaya T, Kyo S, Maida Y et al. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene 2003 22 2352 2360.
Costello JF, Plass C. Methylation matters. J. Med. Genet. 2001 38 285 30.