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Mol. Hum. Reprod. Advance Access originally published online on August 16, 2008
Molecular Human Reproduction 2008 14(9):547-554; doi:10.1093/molehr/gan046
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts

B. Novakovic1, V. Rakyan3, H.K. Ng1,2, U. Manuelpillai4, C. Dewi1, N.C. Wong1,2, R. Morley1, T. Down5, S. Beck6, J.M. Craig1,2 and R. Saffery1,2,7

1Developmental Epigenetics Research, Murdoch Children's Research Institute, Royal Children's Hospital, VIC 3052, Australia 2Department of Paediatrics, University of Melbourne Parkville, VIC 3052, Australia 3 Institute of Cell and Molecular Science, Barts and the London, 4 Newark Street, London E1 2AT, UK 4 Monash Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia 5 Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK 6 UCL, Cancer Institute, University College London, London WC1E 6DD, UK

7 Correspondence address. Tel: +61-03-8341 6341; E-mail: richard.saffery{at}mcri.edu.au

Human placentation displays many similarities with tumourigenesis, including rapid cell division, migration and invasion, overlapping gene expression profiles and escape from immune detection. Recent data have identified promoter methylation in the Ras association factor and adenomatous polyposis coli tumour suppressor genes as part of this process. However, the extent of tumour-associated methylation in the placenta remains unclear. Using whole genome methylation data as a starting point, we have examined this phenomenon in placental tissue. We found no evidence for methylation of the majority of common tumour suppressor genes in term placentas, but identified methylation in several genes previously described in some human tumours. Notably, promoter methylation of four independent negative regulators of Wnt signalling has now been identified in human placental tissue and purified trophoblasts. Methylation is present in baboon, but not in mouse placentas. This supports a role for elevated Wnt signalling in primate trophoblast invasiveness and placentation. Examination of invasive choriocarcinoma cell lines revealed altered methylation patterns consistent with a role of methylation change in gestational trophoblastic disease. This distinct pattern of tumour-associated methylation implicates a coordinated series of epigenetic silencing events, similar to those associated with some tumours, in the distinct features of normal human placental invasion and function.

Key words: placenta/cytotrophoblasts/DNA methylation/Wnt signalling/choriocarcinoma

Submitted on June 19, 2008; resubmitted on July 31, 2008; accepted on August 6, 2008.


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