Translational Research Centre
The Translational Research Centre within the Department of Women’s Cancer, IfWH, has a specialist interest in increasing understanding of the development of women specific cancer, both in women who inherit known genetic mutations, but also in the vast majority of women who do not. Since genetic predisposition only accounts for a limited proportion of women specific cancer, e.g. BRCA mutations account for approximately 5-10% of breast cancer, and 10-15% of ovarian cancer cases, deciphering the role of our environment and lifestyle in cancer formation is fundamental in allowing researchers and clinicians to develop clinical tests of benefit to ALL women. The translational research group has a research emphasis on the ‘epigenetics’ of women specific cancer because the ‘epigenome’ is considered to be the interface between our environment and our genes and therefore potentially explains the development of non-inherited disease. For a video explanation of epigenetics and cancer please click here.
We study all four major women specific cancers: ovarian, breast, endometrial and cervical cancer, and have numerous ongoing research activities, including our ‘EPI-FEM’ programme of research designed to generate new knowledge about women specific cancer and facilitate development of non-invasive tests for:
- Risk Prediction – identifying epigenetic and other biomarkers that are associated with a woman’s risk to develop cancer in the future.
- Early Detection – wherever possible, detecting cancer at an earlier stage will increase chances of recovery and ultimately survival.
- Treatment Prediction – finding ways to discriminate between patients who will benefit from specific treatment versus those who will not means that more women will receive appropriate treatment from which they will benefit on an individual level.
To achieve these aims it is crucial that we understand the origins of cancer. The cell from which breast, endometrial and cervical cancer arise is well understood but that for ovarian cancer is less so. Ovarian cancer is all too often diagnosed at late stage when survival is poor and hence it is difficult to identify and study early cellular morphology in this disease. The complexity of ovarian cancer suggests that this disease arises from multiple cellular origins and not necessarily from the cells surrounding the ovary. Molecular, histological and epidemiological evidence suggests that the origin of ovarian cancer potentially resides in the Mullerian epithelium (See Figure 1). Increased understanding and clarification of the origins of ovarian cancer through epigenetic analysis is a research cornerstone of The Women’s Cancer Translational Research Group.
Epigenetics – Lay Version
Epigenetics literally means ‘upon’ genetics and describes a series of biological processes that affect how our genes behave. Epigenetic processes play a vital role in early and healthy development and are responsible for the cellular diversity throughout our bodies, i.e. whilst all of our cells possess an identical genetic code they both appear and function differently, e.g. our cells in our skin look different and perform a different purpose to those in our bones. This is possible because epigenetic mechanisms turn specific sets of genes ‘on’ and ‘off’ and this determines the cell type. Genes – stretches of DNA that encode a specific protein – are switched ‘on’ and ‘off’ through epigenetic control of gene accessibility, e.g. genes within exposed areas of DNA are considered active (switched ‘on’) whilst those in more densely compacted regions are considered to be inactive (‘switched off’). Epigenetics is therefore important in maintaining health but can become deregulated in diseases including cancer. Click here for a video explaining the concept of epigenetics and cancer.
Epigenetic mechanisms are collectively referred to as the ‘epigenome’ and include one of the best studied epigenetic processes called, ‘DNA methylation’. DNA methylation has been shown to be dramatically altered in cancer tissue and can often be found in normal tissue in areas adjacent to cancer. Furthermore epigenetic mechanisms are responsive to our environment which in turn affects our risk to develop cancer and other disease. Our environmental exposures during development in the womb and after birth, as well as our diet and lifestyle all affect our cancer risk (See Figure 1). Accumulation of epigenetic changes as we age could therefore explain the vast majority of cancer that occurs in women who do not carry a predisposing genetic mutation and furthermore represent valuable biomarkers for disease risk.
Epigenetics provides an explanation for differences in susceptibility to disease between monozygotic twins or cloned animals despite identical DNA sequences. In eukaryotic cells epigenetic modifications are encoded via two primary modes which differ dramatically in their information content: Histone modification and DNA methylation (DNAm). The process of DNAm involves the addition of a methylation group to the fifth carbon of the cytosine ring to form 5-methylcytosine (5meC). Methylation of cytosine occurs when the base precedes a guanosine in the DNA sequence. These ‘CpG dinucleotides’ are uncommon in the vertebrate genome except in small stretches of DNA termed CpG islands, usually 500 to 2,000 base pairs in length, that are frequently located in and around the transcription start sites of genes. Methylation of these CpG islands is usually associated with silencing of the respective gene.
Over the past few years the epigenetic landscape has become extensively studied and more detailed definitions established. CpG island ‘shores’ have been described (CpG clusters that occur outside and up to 2Kb of CpG islands) and have been shown to be important in tissue specific gene expression but also differential methylation occurring in cancer. The tissue specific nature of DNA methylation means that methylation analyses using samples from established biobanks, i.e. whole blood collections would be ineffective owing to cellular heterogeneity of white blood cell types. Consequently, novel prospective tissue specific collections (EPIFEMPRO and EPIFEMGEN) are required to facilitate the optimal discovery of cancer specific differentially methylated regions (DMRs) for clinical development.
The Epigenetic Stem Cell Model of Cancer
In 2007, we and others, published evidence for an ‘epigenetic stem cell model’ of cancer. Embryonic stem cells rely on Polycomb group (PcG) proteins to reversibly repress genes required for differentiation. On cellular differentiation specific gene sets are re-expressed after removal of the PcG proteins from these genes.
We reported (Widschwendter et al Nature Genetics 2007) that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets (See Figure 1), supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing as a consequence of this acquired DNA methylation. The model further suggests that as a result of this permanent silencing the stem cell persistently self-replicates owing to an inability to differentiate increasing the risk of subsequent malignant transformation. The observation of an overlap of cancer specific differential methylation and tissue specific methylation at CpG island shores further supports this model.
EFI-FEM (Epigenetics and Female Cancer) Research Programmes
EPIFEMCARE - Epigenetics For Female Personalised Cancer Care. EPIFEMCARE is funded by the EU FP7 programme and is an academic-industrial collaboration that aims to develop new methods for screening, diagnosis and personalised treatment of breast and ovarian cancers.
EPIFEMPRO - EpiFemPro (Epigenetics for Female Malignancies – Prediction of Risk programme) is focused on the discovery of epigenetic biomarkers that determine a woman’s risk to develop a women specific cancer.
EPIFEMGEN - EpiFemGen (Epigenetics of Female Malignancies with Genetic Predisposition): This element of the EpiFem programme involves the study of hormonal, genetic and epigenetic changes in cells and body fluids of women who are known to be genetically predisposed to breast, ovarian and womb/uterine cancers.
Prof Martin Widschwendter
Head of Department of Women's Cancer, Consultant Gynaecological Oncologist
Miss Allison Jones
Dr Kantaraja Chindera
Dr Iona Evans
Mrs Shohreh Ghazali
Dr Daniel Reisel
Funding, Support and Links
The Eve Appeal
The Eve Appeal is a registered charity, formed in 2005. Since then, they have worked hard to raise money to fund the world-class research programme at the Department of Women's Cancer based at University College London (UCL).
The Department's vital and much-needed research will benefit women in the UK and worldwide.
Eve Appeal www.eveappeal.org.uk/
The European Commission Framework Programme 7 (FP7)
EpifemCare (Epigenetics for Female personalized cancer Care)
The EpiFemCare project is being conducted by a pan-European consortium, which was formed in November 2012, and involves 5 European countries. The project is establishing and clinically validating a series of blood tests based upon biochemical changes detected in DNA released from ovarian and breast cancers.
National Institute for Health and Research (NIHR)
Achieving The Translational Potential Of The UCL-UKCTOCS Cohort And Biobank In Disease Risk Assessment, Screening And Prognostic Prediction
Köbel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, Deen S, Bowtell DD, Odunsi K, Menon U, Morrison C, Lele S, Bshara W, Sucheston L, Beckmann MW, Hein A, Thiel FC, Hartmann A, Wachter DL, Anglesio MS, Høgdall E, Jensen A, Høgdall C, Kalli KR, Fridley BL, Keeney GL, Fogarty ZC, Vierkant RA, Liu S, Cho S, Nelson G, Ghatage P, Gentry-Maharaj A, Gayther SA, Benjamin E, Widschwendter M, Intermaggio MP, Rosen B, Bernardini MQ, Mackay H, Oza A, Shaw P, Jimenez-Linan M, Driver KE, Alsop J, Mack M, Koziak JM, Steed H, Ewanowich C, DeFazio A, Chenevix-Trench G, Fereday S, Gao B, Johnatty SE, George J, Galletta L; AOCS Study Group, Goode EL, Kjær SK, Huntsman DG, Fasching PA, Moysich KB, Brenton JD, Kelemen LE. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. (2014 Dec 9); 111(12):2297-2307. doi: 10.1038/bjc.2014.567. Epub 2014 Oct 30.
Loddo M, Andryszkiewicz J, Rodriguez-Acebes S, Stoeber K, Jones A, Dafou D, Apostolidou S, Wollenschlaeger A, Widschwendter M, Sainsbury R, Tudzarova S, Williams GH. Pregnancy-associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer. J Pathol. (2014 Aug); 233(4):344-56. doi: 10.1002/path.4393.
Jiao Y, Widschwendter M, Teschendorff AE. A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies functional gene modules under epigenetic control. Bioinformatics (2014 Aug 15); 30(16):2360-6. doi: 10.1093/bioinformatics/btu316. Epub 2014 May 2.
Teschendorff AE, Liu X, Caren H, Pollard SM, Beck S, Widschwendter M, Chen L. The Dynamics of DNA Methylation Covariation Patterns in Carcinogenesis. PLoS Comput Biol. (2014 Jul 10); 10(7): e1003709. doi: 10.1371/journal.pcbi.1003709. eCollection 2014.
Anjum S, Fourkala E-O, Zikan M, Wong A, Gentry-Maharaj A, Jones A, Hardy R, Cibula D, Kuh D, Jacobs IJ, Teschendorff AE, Menon U, Widschwendter M. A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival. Genome Med. (2014 Jun 27); 6(6):47. doi: 10.1186/gm567. eCollection 2014.
Almouzni G, Altucci L, Amati B, Ashley N, Baulcombe D, Beaujean N, Bock C, Bongcam-Rudloff E, Bousquet J, Braun S, Paillerets BB, Bussemakers M, Clarke L, Conesa A, Estivill X, Fazeli A, Grgurević N, Gut I, Heijmans BT, Hermouet S, Houwing-Duistermaat J, Iacobucci I, Ilaš J, Kandimalla R, Krauss-Etschmann S, Lasko P, Lehmann S, Lindroth A, Majdič G, Marcotte E, Martinelli G, Martinet N, Meyer E, Miceli C, Mills K, Moreno-Villanueva M, Morvan G, Nickel D, Niesler B, Nowacki M, Nowak J, Ossowski S, Pelizzola M, Pochet R, Potočnik U, Radwanska M, Raes J, Rattray M, Robinson MD, Roelen B, Sauer S, Schinzer D, Slagboom E, Spector T, Stunnenberg HG, Tiligada E, Torres-Padilla ME, Tsonaka R, Soom AV, Vidaković M, Widschwendter M. Relationship between genome and epigenome - challenges and requirements for future research. BMC Genomics (2014 Jun 18); 15:487. doi:10.1186/1471-2164-15-487.
Nunes N, Ambler G, Foo X, Naftalin J, Widschwendter M, Jurkovic D. Use of the IOTA Simple Rules for the diagnosis of ovarian cancer: a Meta-Analysis. Ultrasound Obstet Gynecol. (2014 Jun 11). doi: 10.1002/uog.13437. [Epub ahead of print].
Wittenberger T, Sleigh S, Reisel D, Zikan M, Wahl B, Alunni-Fabbroni M, Jones A, Evans I, Koch J, Paprotka T, Lempiäinen H, Rujan T, Rack B, Cibula D, Widschwendter M. DNA methylation markers for early detection of women’s cancer – promise and challenges. Epigenomics (2014 Jun); 6(3):311-327.
Del Rincón SV*, Widschwendter M*, Sun D, Ekholm-Reed S, Tat J, Teixeira LK, Ellederova Z, Grolieres E, Reed SI, Spruck C. Cks Overexpression Enhances Chemotherapeutic Efficacy by Overriding DNA Damage Checkpoints. Oncogene (2014 May 26). doi: 10.1038/onc.2014.137. [Epub ahead of print]. *equally contributed.
Tan Y, Sun D, Jiang W, Klotz-Noack K, Vashisht AV, Wohlschlegel J, Widschwendter M, Spruck C. PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes its Dysregulation in Cancer. Cancer Res. (2014 Apr 1); 74(7):2006-14. doi: 10.1158/0008-5472.CAN-13-1263. Epub 2014 Feb 7.
Hoivik EA, Kusonmano K, Halle MK, Berg A, Wik E, Werner HM, Petersen K, Oyan AM, Kalland KH, Krakstad C, Trovik J, Widschwendter M, Salvesen HB. Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene. Oncotarget (2014 Feb 28); 5(4):1052-61.
Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, Mould T, West J, Zikan M, Cibula D, Fiegl H, Lee S-H, Wik E, Hadwin R, Arora R, Lemech C, Turunen H, Pakarinen P, Jacobs IJ, Salvesen HB, Bagchi MK, Bagchi IC, Widschwendter M. Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development. PLoS MED. (2013 Nov 12); 10(11): e1001551.
Banerji CR, Miranda-Saavedra D, Severini S, Widschwendter M, Enver T, Zhou JX, Teschendorff AE. Cellular network entropy as the energy potential in Waddington’s differentiation landscape. Scientific Reports (2013 Oct 24); 3:3039. doi: 10.1038/srep03039.
Widschwendter M, Rosenthal AN, Philpott S, Rizzuto I, Fraser L, Hayward J, Intermaggio MP, Edlund CK, Ramus SJ, Gayther SA, Dubeau L, Fourkala EO, Zaikin A, Menon U, and Jacobs IJ. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. The Lancet Oncology (2013 Nov); 14(12): 1226–32. Published Online October 17, 2013. http://dx.doi.org/10.1016/ S1470-2045(13)70448-0.
Nunes N, Ambler G, Hoo WL, Naftalin J, Foo X, Widschwendter M, Jurkovic D. A Prospective Validation of the IOTA Logistic Regression Models (LR1 and LR2) in Comparison to Subjective Pattern Recognition for the Diagnosis of Ovarian Cancer. Int J Gynecol Cancer (2013 Nov); 23(9):1583-9. doi: 10.1097/IGC.0b013e3182a6171a.
West J, Widschwendter M, Teschendorff AE. Distinctive topology of age-associated epigenetic drift in the human interactome. Proc Natl Acad Sci USA (2013 Aug 27); 110(35):14138-43. doi: 10.1073/pnas.1307242110. Epub 2013 Aug 12.
Bartlett TE, Zaikin A, Olhede SC, West J, Teschendorff AE, Widschwendter M. Corruption of the intra-gene DNA methylation architecture is a hallmark of cancer. PLoS One (2013 Jul 16); 8(7):e68285. doi: 10.1371/journal.pone.0068285. Print 2013.
Cepeda D, Ng HF, Sharifi HR, Mahmoudi S, Cerrato VS, Fredlund E, Magnusson K, Nilsson H, Malyukova A, Rantala J, Klevebring D, Viñals F, Bhaskaran N, Zakaria SM, Rahmanto AS, Grotegut S, Nielsen ML, Szigyarto CA, Sun D, Lerner M, Navani S, Widschwendter M, Uhlén M, Jirström K, Pontén F, Wohlschlegel J, Grandér D, Spruck C, Larsson LG, Sangfelt O. CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. EMBO Mol Med. (2013 Jul); 5(7):999-1018. doi: 10.1002/emmm.201202341. Epub 2013 Jun 14.
Doufekas K, Hadwin R, Kandimalla R, Jones A, Mould T, Crowe S, Olaitan A, Macdonald N, Fiegl H, Wik E, Salvesen HB, Widschwendter M. GALR1 Methylation in Vaginal Swabs Is Highly Accurate in Identifying Women With Endometrial Cancer. Int J Gynecol Cancer (2013 Jul); 23(6): 1050-5. doi: 10.1097/IGC.0b013e3182959103.
Widschwendter M, Jones A, Teschendorff AE. Epigenetics makes its mark on women-specific cancers--an opportunity to redefine oncological approaches? Gynecol Oncol. (2013 Jan); 128(1):134-43. doi: 10.1016/j.ygyno.2012.09.027. Epub 2012 Oct 1.
Nunes N, Foo X, Widschwendter M, Jurkovic D. A randomised controlled trial comparing surgical intervention rates between two protocols for the management of asymptomatic adnexal tumours in postmenopausal women. BMJ Open (2012 Dec 11); 2(6). doi:pii: e002248. 10.1136/bmjopen-2012-002248. Print 2012.
Balogun N, Forbes A, Widschwendter M, Lanceley A. Noninvasive nutritional management of ovarian cancer patients: beyond intestinal obstruction. Int J Gynecol Cancer (2012 Jul); 22(6):1089-95. doi: 10.1097/IGC.0b013e318256e4d3.
Teschendorff AE and Widschwendter M. Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions. Bioinformatics (2012 Jun 1); 28(11):1487-94. doi: 10.1093/bioinformatics/bts170. Epub 2012 Apr 6.
Fourkala EO, Gentry-Maharaj A, Burnell M, Ryan, A, Manchanda R, Dawnay A, Jacobs I, Widschwendter M, Menon U. Histological confirmation of breast cancer registration and self-reporting in England and Wales: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening. British Journal of Cancer (2012 Jun 5); 106(12):1910-6. doi: 10.1038/bjc.2012.155. Epub 2012 May 17.
Zhuang J, Widschwendter M, Teschendorff AE. A comparison of feature selection and classification methods in DNA methylation studies using the Illumina Infinium platform. BMC Bioinformatics (2012 Apr 24); 13:59. doi: 10.1186/1471-2105-13-59.
Fourkala EO, Zaikin A, Burnell M, Gentry-Maharaj A, Ford J, Gunu R, Soromani C, Hasenbrink G, Jacobs I, Dawnay A, Widschwendter M, Lichtenberg-Fraté H, Menon U. Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women. Endocr Relat Cancer (2012 Apr 10); 19(2):137-47. doi: 10.1530/ERC-11-0310. Print 2012 Apr.
Teschendorff AE, Jones A, Fiegl H, Sargent A, Zhuang J, Kitchener H & Widschwendter M. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Medicine (2012 Mar 27); 4(3):24.
Zhuang J, Jones A, Lee SH, Ng E, Fiegl H, Zikan M, Cibula D, Sargent A, Salvesen HB, Jacobs IJ, Kitchener HC, Teschendorff AE, Widschwendter M. The Dynamics and Prognostic Potential of DNA Methylation Changes at Stem Cell Gene Loci in Women’s Cancer. PLoS Genet. (2012 Feb); 8(2):e1002517. doi: 10.1371/journal.pgen.1002517. Epub 2012 Feb 9.
Rosenthal AN, Heron G, Widschwendter M, Read S, Brunell C, Mould TA. Fooled by the film: delayed diagnosis of incarcerated small-bowel hernia after laparoscopic surgery for endometrial cancer. Int J Gynecol Cancer (2012 Feb); 22(2):337-9. doi: 10.1097/IGC.0b013e31823c244b.
Liberal, V., Martinsson-Ahlzén, H., Liberal, J., Spruck, C., Widschwendter, M., McGowan, C., and Reed SI. Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins. Proc Natl Acad Sci USA (2012 Feb 21); 109(8):2754-9. doi: 10.1073/pnas.1102434108. Epub 2011 Jun 22.
Goebel G, Berger R, Strasak M, Egle D, Mueller-Holzner E, Schmidt S, Rainer J, Presul E, Lang S, Jones A, Widschwendter M and Fiegl H. Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. Brit J Cancer (2012 Jan 3); 106(1):189-98.
Campan M, Moffitt M, Houshdaran S, Shen H, Widschwendter M, Daxenbichler G, Long T, Marth C, Laird-Offringa IA, Press MF, Dubeau L, Siegmund KD, Wu AH, Groshen S, Chandavarkar U, Roman LD, Berchuck A, Pearce CL, Laird PW. Genome-Scale Screen for DNA Methylation-Based Detection Markers for Ovarian Cancer. PLoS One (2011); 6(12):e28141. [
Koukoura O, Sifakis S, Soufla G, Zaravinos A, Apostolidou S, Jones A, Widschwendter M, Spandidos DA. Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction. Int J Mol Med. (2011); 28(4):481-7.
Teschendorff AE, Zhuang J, Widschwendter M. Independent Surrogate Variable Analysis as a tool to deconvolve confounding factors in large-scale microarray profiling studies. Bioinformatics (2011 Jun 1); 27(11):1496-505.
Cibula D, Widschwendter M, Zikan M, Dusek L. Underlying mechanisms of ovarian cancer risk reduction after tubal ligation. Acta Obstet Gynecol Scand. (2011); 90(6):559-63. [IF: 1.850]
Cibula D, Widschwendter M, Dušek L. Tubal Ligation and the Risk of Ovarian Cancer – review and meta-analysis. Hum Reprod Update (2011); 17(1): 55-67.
Koukoura O, Sifakis S, Zaravinos A, Apostolidou S, Jones A, Hajiioannou J, Widschwendter M, Spandidos DA. Hypomethylation along with increased H19 expression in placentas from pregnancies complicated with fetal growth restriction. Placenta (2011); 32(1):51-7.
Akhoondi S, Lindstrom L, Widschwendter M, Corcoran M, Bergh J, Spruck C, Grander D, Sangfelt O. Inactivation of FBXW7/hCDC4-beta expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer. Breast Cancer Res. (2010); 12(6):R105.
Balogun N, Gentry-Maharaj A, Wozniak EL, Lim A, Ryan A, Ramus SJ, Ford J, Burnell M, Widschwendter M, Gessler SF, Gayther SA, Jacobs IJ, Menon U. Recruitment of newly diagnosed ovarian cancer patients proved challenging in a multicentre biobanking study. J Clin Epidemiol. (2010); 64(5):525-30.
Schramek D, Leibbrandt A, Sigl V, Kenner L, Hanada R, Joshi P, Pospisilik JA, Lee H, Aliprantis A, Ormandy C, Glimcher L, Pasparakis M, Khoka R, Widschwendter M, Schett G, and Penninger JM. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature (2010 Nov 4); 468(7320): 98-102.
Goode E, Chenevix-Trench G, Song H, Ramus S , Notaridou M , Lawrenson K, Widschwendter M, et al., Ovarian Cancer Association Consortium. A Genome-Wide Association Study Identifies Susceptibility Loci for Ovarian Cancer at 2q31 and 8q24. Nat Genet. (2010 October); 42(10): 874–879.
del Rincón S, Rogers J, Widschwendter M, Sun D, Sieburg HB, and Spruck C. Development and Validation of a Method for Profiling Post-Translational Modification Activities Using Protein Microarrays. PLoS One (2010 Jun 28); 5(6):e11332. doi: 10.1371/journal.pone.0011332.
Berger R, Fiegl H, Goebel G, Obexer P, Ausserlechner M, Doppler W, Hauser-Kronberger C, Reitsamer R, Egle D, Reimer D, Muller-Holzner E, Jones A & Widschwendter M. Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors. Cancer Sci. (2010); 101: 1059-1066.
Thirlwell C, Eymard M, Feber A, Teschendorff A, Pearce K, Lechner M, Widschwendter M, Beck S. Genome-wide DNA methylation analysis of archival formalin-fixed paraffin-embedded tissue using the Illumina Infinium Human Methylation27 BeadChip. Methods (2010); 52(3): 248-254. [IF: 3.641]
Fourkala EO, Hauser-Kronberger C, Apostolidou S, Burnell M, Jones A, Grall J, Reitsamer R, Fiegl H, Jacobs I, Menon U & Widschwendter M. DNA methylation of polycomb group target genes in cores taken from breast cancer centre and periphery. Breast Cancer Res Treat. (2010); 120: 345-355.
Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, Campan M, Noushmehr H, Bell CG, Maxwell AP, Savage DA, Mueller-Holzner E, Marth C, Kocjan G, Gayther SA, Jones A, Beck S, Wagner W, Laird PW, Jacobs IJ & Widschwendter M. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. (2010 Apr); 20(4): 440-446.
A. Jones, M. Lechner, E.O. Fourkala, R. Kristeleit, M. Widschwendter. Emerging promise of epigenetics and DNA methylation for the diagnosis and management of women's cancers. Epigenomics (2010 Feb); 2(1):9-38. doi: 10.2217/epi.09.47.
Widschwendter M, Apostolidou S, Jones AA, Fourkala EO, Arora R, Pearce CL, Frasco MA, Ayhan A, Zikan M, Cibula D, Iyibozkurt CA, Yavuz E, Hauser-Kronberger C, Dubeau L, Menon U & Jacobs IJ. HOXA methylation in normal endometrium from premenopausal women is associated with the presence of ovarian cancer: a proof of principle study. Int J Cancer (2009); 125: 2214-2218.
Teschendorff AE. Menon U, Gentry-Maharaj A, Ramus SJ, Gayther SA, Apostolidou S, Jones A, Lechner M, Beck S, Jacobs IJ & Widschwendter M. An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One. (2009 dec); 4(12), e8274.
S. Apostolidou, R. Hadwin, M. Burnell, A. Jones, D. Baff, N. Pyndiah, T. Mould, I.J. Jacobs, S. Beddows, G. Kocjan, M. Widschwendter. DNA methylation analysis in liquid-based cytology for cervical cancer screening. Int J Cancer. (2009); 125:2995-3002.
M. Widschwendter, H. Lichtenberg-Frate, G. Hasenbrink, S. Schwarzer, A. Dawnay, A. Lam, U Menon, S. Apostolidou, E. Raum, C. Stegmaier, I.J. Jacobs, H. Brenner. Serum oestrogen receptor alpha and beta bioactivity are independently associated with breast cancer: a proof of principle study. Br J Cancer. (2009); 101:160-5.
M.Widschwendter, S.Apostolidou, E.Raum, D.Rothenbacher, H.Fiegl, U.Menon, C.Stegmaier, I.J.Jacobs, H.Brenner. Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One (2008 Jul 16); 3(7):e2656.
H.Fiegl, A.Jones, C.Hauser-Kronberger, G.Hutarew, R.Reitsamer, R.Jones, M.Dowsett, E.Mueller-Holzner, G.Windbichler, G.Daxenbichler, G.Goebel, C.Ensinger, I.J.Jacobs, M.Widschwendter. Methylated NEUROD1 promoter is a marker for chemonsensitivity in breast cancer. Clin Cancer Res. (2008); 14: 3494-3502.
H.Fiegl, G.Windbichler, E.Mueller-Holzner, G.Goebel, M.Lechner, I.J.Jacobs, M.Widschwendter. HOXA11 DNA methylation – a novel prognostic biomarker in ovarian cancer. Int J Cancer. (2008); 123:725-729.
Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dafou D, Marth C, Mueller-Holzner E, Corcoran M, Dagnell M, Nejad SZ, Nayer BN, Zali MR, Hansson J, Egyhazi S, Petersson F, Sangfelt P, Nordgren H, Grander D, Reed SI, Widschwendter M, Sangfelt O, Spruck C. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. (2007 Oct 1); 67(19):9006-12.
M.Widschwendter. 5-methylcytosine – the fifth base of DNA: The fifth wheel on a car or a highly promising diagnostic and therapeutic target in cancer? Dis Markers. (2007); 23: 1-3.
M.Widschwendter, H.Fiegl, D.Egle, E.Mueller-Holzner, G.Spizzo, C.Marth, D.J.Weisenberger, M.Campan, J.Young, I.Jacobs, P.W.Laird. Epigenetic stem cell signature in cancer. Nat Genet. (2007); 39:157-158.
M.Widschwendter, U.Menon. Circulating methylated DNA: a new generation of tumor markers. Clin Cancer Res. (2006); 12:7205-7208.
C.Spruck, D.Sun, H.Fiegl, C.Marth, E.Mueller-Holzner, G.Goebel, M.Widschwendter, S.I.Reed. Detection of low molecular weight derivatives of cyclin E1 is a function of cyclin E1 protein levels in breast cancer. Cancer Res. (2006); 66:7355-7360.
D.J.Weisenberger, K.D.Siegmund, M.Campan, J.Young, T.I.Long, M.A.Faasse, G.H.Kang, M.Widschwendter, D.Weener, D.Buchanan, H.Koh, L.Simms, M.Barker, B.Leggett, J.Levine, M.Kim, A.J.French, S.N.Thibodeau, J.Jass, R.Haile, P.W.Laird. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. (2006); 38:787-793.
H.Fiegl, S.Millinger, G.Goebel, E.Muller-Holzner, C.Marth, P.W.Laird, M.Widschwendter. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res. (2006); 66:29-33.
G.Goebel, H.M.Muller, H.Fiegl, M.Widschwendter. Gene methylation data--a new challenge for bioinformaticians? Methods Inf Med. (2005); 44:516-519.
H.Fiegl, S.Millinger, E.Mueller-Holzner, C.Marth, C.Ensinger, A.Berger, H.Klocker, G.Goebel, M.Widschwendter. Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res. (2005); 65:1141-1145.
K.Jackson, M.C.Yu, K.Arakawa, E.Fiala, B.Youn, H.Fiegl, E.Muller-Holzner, M.Widschwendter, M.Ehrlich. DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol Ther. (2004); 3:1225-1231.
H.M.Muller, S.Millinger, H.Fiegl, G.Goebel, L.Ivarsson, A.Widschwendter, E.Muller-Holzner, C.Marth, M.Widschwendter. Analysis of methylated genes in peritoneal fluids of ovarian cancer patients: a new prognostic tool. Clin Chem. (2004); 50:2171-2173.
B.Rainer, J.Berger, M.Widschwendter, G.Mitterschiffthaler, G.Putz. [Tumorectomy in conscious patient with suspected pregnancy associated breast cancer under cervical epidural anesthesia]. Anasthesiol Intensivmed Notfallmed Schmerzther. (2004); 39:412-414.
H.M.Muller, H.Fiegl, A.Widschwendter, M.Widschwendter. Prognostic DNA methylation marker in serum of cancer patients. Ann N Y Acad Sci. (2004); 1022:44-49.
M.Widschwendter, G.Jiang, C.Woods, H.M.Muller, H.Fiegl, G.Goebel, C.Marth, E.Muller-Holzner, A.G.Zeimet, P.W.Laird, M.Ehrlich. DNA hypomethylation and ovarian cancer biology. Cancer Res. (2004); 64:4472-4480.
M.Widschwendter, K.D.Siegmund, H.M.Muller, H.Fiegl, C.Marth, E.Muller-Holzner, P.A.Jones, P.W.Laird. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res. (2004); 64:3807-3813.
H.M.Muller, L.Ivarsson, H.Schrocksnadel, H.Fiegl, A.Widschwendter, G.Goebel, S.Kilga-Nogler, H.Philadelphy, W.Gutter, C.Marth, M.Widschwendter. DNA methylation changes in sera of women in early pregnancy are similar to those in advanced breast cancer patients. Clin Chem. (2004); 50:1065-1068.
A.Widschwendter, C.Gattringer, L.Ivarsson, H.Fiegl, A.Schneitter, A.Ramoni, H.M.Muller, A.Wiedemair, S.Jerabek, E.Muller-Holzner, G.Goebel, C.Marth, M.Widschwendter. Analysis of aberrant DNA methylation and human papillomavirus DNA in cervicovaginal specimens to detect invasive cervical cancer and its precursors. Clin Cancer Res. (2004); 10:3396-3400.
H.Fiegl, C.Gattringer, A.Widschwendter, A.Schneitter, A.Ramoni, D.Sarlay, I.Gaugg, G.Goebel, H.M.Muller, E.Mueller-Holzner, C.Marth, M.Widschwendter. Methylated DNA collected by tampons--a new tool to detect endometrial cancer. Cancer Epidemiol Biomarkers Prev. (2004); 13:882-888.
H.M.Muller, A.Widschwendter, H.Fiegl, G.Goebel, A.Wiedemair, E.Muller-Holzner, C.Marth, M.Widschwendter. A DNA methylation pattern similar to normal tissue is associated with better prognosis in human cervical cancer. Cancer Lett. (2004); 209:231-236.
A.Widschwendter, H.M.Muller, M.M.Hubalek, A.Wiedemair, H.Fiegl, G.Goebel, E.Mueller-Holzner, C.Marth, M.Widschwendter. Methylation status and expression of human telomerase reverse transcriptase in ovarian and cervical cancer. Gynecol Oncol. (2004); 93:407-416.
H.M.Muller, M.Oberwalder, H.Fiegl, M.Morandell, G.Goebel, M.Zitt, M.Muhlthaler, D.Ofner, R.Margreiter, M.Widschwendter. Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet. (2004); 363:1283-1285.
M.M.Hubalek, A.Widschwendter, M.Erdel, A.Gschwendtner, H.M.Fiegl, H.M.Muller, G.Goebel, E.Mueller-Holzner, C.Marth, C.H.Spruck, S.I.Reed, M.Widschwendter. Cyclin E dysregulation and chromosomal instability in endometrial cancer. Oncogene. (2004); 23:4187-4192.
B.Del Frari, P.Pulzl, T.Schoeller, M.Widschwendter, G.Wechselberger. Pregnancy as a tissue expander in the correction of a scar deformity. Am J Obstet Gynecol. (2004); 190:579-580.
S.Ekholm-Reed, C.H.Spruck, O.Sangfelt, F.van Drogen, E.Mueller-Holzner, M.Widschwendter, A.Zetterberg, S.I.Reed. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer. Cancer Res. (2004); 64:795-800.
A.Widschwendter, H.M.Muller, H.Fiegl, L.Ivarsson, A.Wiedemair, E.Muller-Holzner, G.Goebel, C.Marth, M.Widschwendter. DNA methylation in serum and tumors of cervical cancer patients. Clin Cancer Res. (2004); 10:565-571.
A.Widschwendter, L.Ivarsson, A.Blassnig, H.M.Muller, H.Fiegl, A.Wiedemair, E.Muller-Holzner, G.Goebel, C.Marth, M.Widschwendter. CDH1 and CDH13 methylation in serum is an independent prognostic marker in cervical cancer patients. Int J Cancer. (2004); 109:163-166.
H.M.Muller, A.Widschwendter, H.Fiegl, L.Ivarsson, G.Goebel, E.Perkmann, C.Marth, M.Widschwendter. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res. (2003); 63:7641-7645.
H.M.Muller, H.Fiegl, G.Goebel, M.M.Hubalek, A.Widschwendter, E.Muller-Holzner, C.Marth, M.Widschwendter. MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. Br J Cancer. (2003); 89:1934-1939.
H.M.Muller, M.Widschwendter. Methylated DNA as a possible screening marker for neoplasticdisease in several body fluids. Expert Rev Mol Diagn. (2003); 3:443-458.
M.Ehrlich, G.Jiang, E.Fiala, J.S.Dome, M.C.Yu, T.I.Long, B.Youn, O.S.Sohn, M.Widschwendter, G.E.Tomlinson, M.Chintagumpala, M.Champagne, D.Parham, G.Liang, K.Malik, P.W.Laird. Hypomethylation and hypermethylation of DNA in Wilms tumors. Oncogene. (2002); 21:6694-6702.
C.H.Spruck, H.Strohmaier, O.Sangfelt, H.M.Muller, M.Hubalek, E.Muller-Holzner, C.Marth, M.Widschwendter, S.I.Reed. hCDC4 gene mutations in endometrial cancer. Cancer Res. (2002); 62:4535-4539.
M.Widschwendter, P.A.Jones. DNA methylation and breast carcinogenesis. Oncogene. (2002); 21:5462-5482.
A.G.Zeimet, E.Muller-Holzner, A.Schuler, G.Hartung, J.Berger, M.Hermann, M.Widschwendter, J.M.Bergelson, C.Marth. Determination of molecules regulating gene delivery using adenoviral vectors in ovarian carcinomas. Gene Ther. (2002); 9:1093-1100.
M.Widschwendter, P.A.Jones. The potential prognostic, predictive, and therapeutic values of DNA methylation in cancer. Commentary re: J. Kwong et al., Promoter hypermethylation of multiple genes in nasopharyngeal carcinoma. Clin. Cancer Res., 8: 131-137, 2002, and H-Z. Zou et al., Detection of aberrant p16 methylation in the serum of colorectal cancer patients. Clin. Cancer Res. 8: 188-191, 2002. Clin Cancer Res. (2002); 8:17-21.
M.Widschwendter, J.Berger, H.M.Muller, A.G.Zeimet, C.Marth. Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer. J Mammary Gland Biol Neoplasia. (2001); 6:193-201.
A.Amberger, H.Weiss, T.Haller, G.Kock, M.Hermann, M.Widschwendter, R.Margreiter. A subpopulation of mitochondria prevents cytosolic calcium overload in endothelial cells after cold ischemia/reperfusion. Transplantation. (2001); 71:1821-1827.
H.Weiss, A.Amberger, M.Widschwendter, R.Margreiter, D.Ofner, P.Dietl. Inhibition of store-operated calcium entry contributes to the anti-proliferative effect of non-steroidal anti-inflammatory drugs in human colon cancer cells. Int J Cancer. (2001); 92:877-882.
A.G.Zeimet, S.Stadlmann, C.Natoli, M.Widschwendter, M.Hermann, B.Abendstein, G.Daxenbichler, F.A.Offner, S.Iacobelli, C.Marth. Peritoneal mesothelial cells as a significant source of ascitic immunostimulatory protein 90K. Anticancer Res. (2000); 20:4507-4511.
A.M.Bergant, M.Widschwendter, N.Sepp. Bilateral nipple ulcers in a breastfeeding woman: a manifestation of Behcet's disease? BJOG. (2000); 107:1320-1322.
A.G.Zeimet, K.Riha, J.Berger, M.Widschwendter, M.Hermann, G.Daxenbichler, C.Marth. New insights into p53 regulation and gene therapy for cancer. Biochem Pharmacol. (2000); 60:1153-1163.
B.Abendstein, A.Zeimet, M.Rieger, M.Widschwendter, F.Offner, E.Muller-Holzner. Alveolar echinococcosis with bulky peritoneal spread--a rare but important diagnosis in gynaecological practice. BJOG. (2000); 107:695-697.
M.Widschwendter, J.Berger, M.Hermann, H.M.Muller, A.Amberger, M.Zeschnigk, A.Widschwendter, B.Abendstein, A.G.Zeimet, G.Daxenbichler, C.Marth. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst. (2000); 92:826-832.
J.Berger, A.Telser, M.Widschwendter, E.Muller-Holzner, G.Daxenbichler, C.Marth, A.G.Zeimet. Expression of retinoic acid receptors in non-neoplastic epithelial disorders of the vulva and normal vulvar skin. Int J Gynecol Pathol. (2000); 19:95-102.
B.Abendstein, C.Marth, E.Muller-Holzner, M.Widschwendter, G.Daxenbichler, A.G.Zeimet. Clinical significance of serum and ascitic p53 autoantibodies in epithelial ovarian carcinoma. Cancer. (2000); 88:1432-1437.
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