Top

Cellular Oncology

Published in:

01-12-2012 | Original Paper

Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development

Authors: Rahul Bhagat, Shilpa Chadaga, C. S. Premalata, G. Ramesh, C. Ramesh, V. R. Pallavi, Lakshmi Krishnamoorthy

Published in: Cellular Oncology | Issue 6/2012

Abstract

Purpose

Tumor suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer development. The aim of this study was to assess the extent of methylation of the RASSF1A and APC TSG promoters in ovarian epithelial adenomas, low malignant potential tumours and carcinomas in order to reveal a role for epigenetic TSG silencing in the development of these ovarian malignancies.

Method

The promoter methylation status of the RASSF1A and APC genes was assessed in 19 benign cystadenomas, 14 low malignant potential (LMP) tumours, and 86 carcinomas using methylation specific PCR (MSP).

Results

The methylation frequencies of the RASSF1A and APC gene promoters in benign cystadenomas were found to be 37 % and 16 %, respectively. The LMP tumours exhibited RASSF1A and APC gene promoter methylation frequencies of 50 % and 28 %, respectively, whereas the carcinomas exhibited methylation frequencies of 58 % and 29 %, respectively. Methylation of either the RASSF1A or the APC gene promoter was encountered in 58 % of the invasive carcinomas.

Conclusion

The observed aberrant methylation frequencies of the RASSF1A and APC gene promoters indicate that an accumulation of epigenetic events at these specific TSG promoters may be associated with the malignant transformation of benign cystadenomas and LMP tumours to carcinomas.

D.M. Parkin, F. Bray, J. Ferlay et al., Global cancer statistics, 1998. CA Cancer J. Clin. 55, 74–108 (2005)PubMedCrossRef

A. Nandakumar, Biennial Report (1990–96) of National Cancer Registry Programme, Indian Council of Medical Research (National Printing Press, New Delhi, 2001)

C.C. Boring, T.S. Squires, T. Tong, S. Montgomery, Cancer statistics, 1994. CA Cancer J. Clin. 44, 7–26 (1994)PubMedCrossRef

S.H. Wei, C. Balch, H.H. Paik, Y.S. Kim, R.L. Baldwin, S. Liyanarachchi et al., Prognostic DNA methylation biomarkers in ovarian cancer. Clin. Cancer Res. 12, 2788–2794 (2006)PubMedCrossRef

P.A. Jones, S.B. Baylin, The epigenomics of cancer. Cell 128, 683–692 (2007)PubMedCrossRef

P.M. Warnecke, T.H. Bestor, Cytosine methylation and human cancer. Curr. Opin. Oncol. 12, 68–73 (2000)PubMedCrossRef

S.B. Baylin, J.G. Herman, DNA Hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 16, 168–174 (2000)PubMedCrossRef

P.B. Makarla, M.H. Saboorian, R. Ashfaq, K.O. Toyooka, S. Toyooka, J.D. Minna et al., Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin. Cancer Res. 11, 5365–5369 (2005)PubMedCrossRef

I. Ibanez de Caceres, C. Battagli, M. Esteller, J.G. Herman, E. Dulaimi, M.I. Edelson et al., Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 64, 6476–6481 (2004)PubMedCrossRef

10.

J.H. Yoon, R. Dammann, G.P. Pfeifer, Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int. J. Cancer 94, 212–217 (2001)PubMedCrossRef

11.

A. Rathi, A.K. Virmani, J.O. Schorge, K.J. Elias, R. Maruyama, J.D. Minna et al., Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin. Cancer Res. 8, 3324–3331 (2002)PubMed

12.

A. Agathanggelou, S. Honorio, D.P. Macartney, A. Martinez, A. Dallol, J. Rader et al., Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene 20, 1509–1518 (2001)PubMedCrossRef

13.

M. Yanokura, K. Banno, M. Kawaguchi, N. Hirao, A. Hirasawa, N. Susumu et al., Relationship of aberrant DNA Hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer. Oncol Rep. 17, 41–48 (2007)PubMed

14.

M. Wallner, A. Herbst, A. Behrens, A. Crispin, P. Stieber, B. Goke et al., Methylation ofserum DNA is an independent prognostic marker in colorectal cancer. Clin. Cancer Res. 12, 7347–7352 (2006)PubMedCrossRef

15.

A. Agathanggelou, W.N. Cooper, F. Latif, Role of the Ras-association domain family1 tumor suppressor gene in human cancers. Cancer Res. 65, 3497–3508 (2005)PubMedCrossRef

16.

G.P. Pfeifer, R. Dammann, Methylation of the tumor suppressor gene RASSF1A in human tumors. Biochemistry (Mosc) 70, 576–583 (2005)CrossRef

17.

L. Liu, R.R. Broaddus, J.C. Yao et al., Epigenetic alterations in neuroendocrine tumors: methylation of RASassociation domain family1, isoform A and p16 genes are associated with metastasis. Mod. Pathol. 18, 1632–1640 (2005)PubMed

18.

D.G. Burbee, E. Forgacs, M.S. Zochbauer et al., Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst. 93, 691–699 (2001)PubMedCrossRef

19.

R. Dammann, C. Li, J.H. Yoon, P.L. Chin, S. Bates, G.P. Pfeifer, Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat. Genet. 25, 315–319 (2000)PubMedCrossRef

20.

K. Dreijerink, E. Braga, I. Kuzmin et al., The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc Natl Acad Sci USA 98, 7504–7509 (2001)PubMedCrossRef

21.

Y.L. Choi, S.Y. Kang, Y.K. Shin, J.S. Choi, S.H. Kim, S.J. Lee et al., Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas. Virchows Arch. 448, 331–336 (2006)PubMedCrossRef

22.

M. Cul'bova, Z. Lasabova, A. Stanclova, P. Tilandyova, P. Zubor, R. Fiolka et al., Methylation of selected tumor-supressor genes in benign and malignant ovarian tumors. Ceska Gynekol 76(4), 274–279 (2011)PubMed

23.

S. Kassler, H. Donninger, M.J. Birrer, G.J. Clark, RASSF1A and the taxol response in ovarian cancer. Mol. Biol. Int (2012). doi:10.1155/2012/263267

24.

P.J. Morin, B. Vogelstein, K.W. Kinzler, Apoptosis and APC in colorectal tumorigenesis. Proc Natl Acad Sci USA 93, 7950–7954 (1996)PubMedCrossRef

25.

G.H. Baeg, A. Matsumine, T. Kuroda et al., The tumor suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. EMBO J. 14, 5618–5625 (1995)PubMed

26.

M. Ilyas, J. Staub, I.P. Tomlinson, W.F. Bodmer, Genetic pathways in colorectal and other cancers. Eur. J. Cancer 35, 1986–2002 (1999)PubMedCrossRef

27.

S.M. Powell, N. Zilz, Y. Beazer-Barclay et al., APC mutations occur early during colorectal tumorigenesis. Nature (Lond.) 359, 235–237 (1992)CrossRef

28.

S. Honorio, A. Agathanggelou, M. Schuermann, W. Pankow, P. Viacava, E.R. Maher et al., Detection of RASSF1A aberrant promoter hypermethylation in sputum from chronic smokers and ductal carcinoma in situ from breast cancer patients. Oncogene 22, 147–150 (2003)PubMedCrossRef

29.

I.H. Wong, J. Chan, J. Wong, P.K. Tam, Ubiquitous aberrant RASSF1A promoter methylation in childhood neoplasia. Clin. Cancer Res. 10, 994–1002 (2004)PubMedCrossRef

30.

M.C.Y. Xing, E. Mambo, G. Tallini, R. Udelsman, P.W. Ladenson, D. Sidransky, Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res. 64, 1664–1668 (2004)PubMedCrossRef

31.

S. Eissa, M. Swella, I.M. El-Khouly, S.K. Kassim, H. Shehata, A. Mansour et al., Aberrant methylation of RARbeta2 and APC genes in voided urine as molecular markers for early detection of bilharzial and nonbilharzial bladder cancer. Cancer Epidemiol Biomarkers Prev. 20(8), 1657–1664 (2011)PubMedCrossRef

32.

H.Y. Yoon, S.K. Kim, Y.W. Kim, H.W. Kang, S.C. Lee, K.H. Ryu et al., Combined hypermethylation of APC andGSTP1 as a molecular marker for prostate cancer: quantitative pyrosequencing analysis. J. Biomol. Screen. (2012). doi:10.1177/1087057112444445

33.

S.E. Russell, W.G. McCluggage, A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes. J. Pathol. 203, 617–619 (2004)PubMedCrossRef

34.

C.J. Link Jr., E. Reed, G. Sarosy, E.C. Kohn, Borderline ovarian tumors. Am. J. Med. 101, 217–225 (1996)PubMedCrossRef

35.

R.E. Scully, Common epithelial tumors of borderline malignancy (carcinomas of low malignant potential). Bull Cancer. 69, 228–238 (1982)PubMed

Title: Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development
Authors: Rahul Bhagat
Shilpa Chadaga
C. S. Premalata
G. Ramesh
C. Ramesh
V. R. Pallavi
Lakshmi Krishnamoorthy
Publication date: 01-12-2012
Publisher: Springer Netherlands
Published in: Cellular Oncology / Issue 6/2012
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-012-0106-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Method

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2012

Interpretation of interlocking key issues of cancer stem cells in malignant solid tumors

Disulfide-stabilized diabody antiCD19/antiCD3 exceeds its parental antibody in tumor-targeting activity

High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients

HIF-1α and NOTCH signaling in ductal and lobular carcinomas of the breast

EGFR status and KRAS/BRAF mutations in intestinal-type sinonasal adenocarcinomas

CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort

Keynote webinar | Spotlight on antibody–drug conjugates in cancer