Analysis of the TES gene in cancer
Molecular Medical Genetics Research Group
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Dr Edward S Tobias (BSc, MBChB, PhD, FRCP) Senior Lecturer and Honorary Consultant in Medical Genetics
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Please visit this University news page and his staff pages for updated information about Dr Tobias
The group aims to improve our understanding of a variety of medical genetic disorders. We are closely linked with the West of Scotland Regional Genetics Service with several projects arising from the molecular investigation of patients with clinical genetic conditions that range from single gene disorders to complex diseases. We have specific interests in genotype-phenotype correlations in individuals with congenital Mullerian abnormalities, the role of the recently identified TES tumour suppressor gene in human cancer, the genes underlying familial joint instability and the molecular genetics of cutaneous malignant melanoma.
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TES gene in cancer
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Molecular genetic analysis of famialial joint instability
Molecular genetic analysis of famialial joint instability
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Cutaneous malignant melanoma
Scottish origin of CDKN2A mutation
Previous students have gone on to successfully gain research-related positions at the Imperial College London, at the University of Cambridge, at Barts and the London and at the Hammersmith Hospital.
Recent Research
Analysis of the TES gene in cancer
We have cloned and characterized a novel multi-tissue tumour suppressor gene, TES, at chromosome 7q31 and excluded, in a Nature Genetics publication, the neighbouring ST7 gene as the important tumour suppressor gene at that locus. The gene encodes a 421 amino acid protein that, unusually, contains a PET domain together with three LIM domains. We detected a profound reduction in growth potential upon expression of transfected TES in HeLa and OVCAR5 cells, derived from cervical and ovarian carcinomas, respectively. In addition, mutation analysis of the coding exons of TES revealed the presence of a frameshift mutation in one allele in the human breast cancer cell line ZR-75, that is predicted to lead to disruption of the second LIM domain and loss of the third. Like several other tumour suppressor genes, TES appears to be inactivated by transcriptional silencing resulting from CpG island methylation or by mutation. An exciting prospect is that since DNA methylation can be reversed by drugs, at least in vitro, these genes may represent future cancer therapy targets. Moreover, an extensive analysis of cell-specific expression levels of the genes which are located within the interval at 7q31 that is defined by several loss of heterozygosity studies, has demonstrated that TES is the strongest candidate TSG in the region. In addition, the in vivo role of the gene as a tumour suppressor has now been confirmed by the significantly higher tumour susceptibility of heterozygous and homozygous TES knockout mice relative to their wild-type littermates. Investigations are underway in our laboratory into the role of TES in human cancer, taking advantage of the excellent facilities and the large number of samples available locally, together with ethical approval. One of my students was recently awarded the university’s Women’s Federation prize for her laboratory work on this gene.
TES protein domains
Domain analysis of the 421-amino acid TES protein by PFAM, showing the relative positions within TES of the PET domain and the three C-terminal LIM domains.
In addition to analysing the TES gene, we have investigated the role of another TSG, NF1, in the molecular basis of gastric carcinoid tumour in neurofibromatosis type 1, recently demonstrating loss of heterozygosity at the NF1 gene locus in the tumour DNA. Other collaborative clinical molecular genetic studies have included an investigation of insulin receptor gene defects in severe insulin resistance, molecular genetic mapping of clinically significant loci on the X chromosome and the clinical and molecular investigation of a DNA repair disorder.
Funding from: GlaxoSmithKline (Clinical Research Fellowship) and Tenovus-Scotland
Molecular genetic analysis of familial joint instability
We are currently investigating the molecular genetic basis of familial large joint instability with recurrent dislocations in the absence of significant skin hyperelasticity. Analysis of specific candidate genes including collagen genes, in the DNA of the affected individuals is being carried out in the first instance by linkage analysis, and results to date have been intriguing. In addition, in collaboration with other European investigators we have recently helped to clarify the role of the collagen gene, COL2A1, and the genotype-phenotype relationship, in the form of genetic skeletal dysplasia known as spondylo-epimetaphyseal dysplasia.
Funding from: Yorkhill Children's Foundation
Cutaneous malignant melanoma
An important focus of my research, a collaboration since August 2006 with Prof Rona MacKie (Dermatology and Public Health), funded by the Chief Scientist Office, is familial cutaneous malignant melanoma (CMM). Our post-doctoral scientist, Dr Julie Lang, has detected mutations in the CDKN2A gene in around one third of almost 70 Scottish CMM families. In addition, with international collaborators, we have demonstrated the Scottish origin of the CDKN2A M53I mutation, present in several melanoma families worldwide. Our work has now been given the rarely-awarded Excellent grading by the Biomedical and Therapeutic Research Committee of the Chief Scientist Office, which also commented that "a complex study had been delivered to high quality".
Funding from: Chief Scientist Office for Scotland
Research Funding
Principal Investigator on the following grants :
- Chief Scientist Office for Scotland Project Grant (since 2006): Identification of high-penetrance gene alterations that predispose to familial melanoma in Scottish Patients. Co-investigator: Prof RM MacKie. Post-doc researcher: Dr J Lang
- Tenovus-Scotland Project Grant (since 2006): Molecular genetic analysis of the putative tumour suppressor gene, TES, in human breast cancer.
- Yorkhill Children's Foundation (since 2007): Molecular genetic investigation of familial joint instability.
- GlaxoWellcome/GlaxoSmithKline (Senior) Clinical Research Fellowship (previously awarded)
- Medical Research Council Training Fellowship (previously awarded)
- Scottish Hospital Endowments Research Trust. Medical Research Foreign Travel Grant: Vanderbilt University School of Medicine (awarded previously)
Co-investigator on the following:
- Epilepsy Research Foundation Project Grant (previously awarded for Genetic Analysis of Familial Idiopathic Epilepsy in Scottish Families)
Selected Publications
Lang J, Tobias ES, Mackie R. (2011, in press). Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma. British Journal of Dermatology
Laugel V, Dalloz C, Durand M, et al. (2010) Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Human Mutation 31:113-26
Mefford HC, Sharp AJ, Baker C, et al. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England J Medicine 359:1685-99
Laugel V, Dalloz C, Tobias ES, Tolmie JL, Martin-Coignard D, Drouin-Garraud V,Valayannopoulos V, Sarasin A, Dollfus H. (2008). COFS syndrome:three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation. Journal of Medical Genetics 45:564-71
Lang J, Hayward N, Goldgar D, Tsao H, Hogg D, Palmer J, Stark M, Tobias ES, Mackie R (2007) The M53I mutation in CDKN2A is a founder mutation that predominates in melanoma patients with Scottish ancestry. Genes Chromosomes Cancer. 46:277-87.
Stewart W, Traynor JP, Cooke A, Griffiths S, Onen NF, Balsitis M, Shah AA, Upadhyaya M, Tobias ES (2007) Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene. Fam Cancer. 6:147-52.
Walter KN, Tansek MZ, Tobias ES, Ikegawa S, Coucke P, Hyland J, Mortier G, Iwaya T, Nishimura G, Superti-Furga A, Unger S (2007) COL2A1-related Skeletal Dysplasias with Predominant Metaphyseal Involvement. Am J Med Genet. 143:161-7.
Tobias, E., Cooke, A., Traynor, J.P., Onen, N., Balsitis, M., Shah, A.A. & Stewart, W (2004) Gastric carcinoid tumour with intragenic marker LOH in neurofibromatosis type 1. Journal of Medical Genetics 41: S50.
Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, D'Haens E, Kleijer WJ, Fery F, van der Zon GC (2003) Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. J Clin Endocrinol Metab. 88:4251-7.
Tobias ES, Tolmie JL, Stephenson JB (2002) Cataplexy in the Prader-Willi syndrome. Arch Dis Child. 87:170.
Hughes KA, Hurlstone AF, Tobias ES, McFarlane R, Black DM (2001) Absence of ST7 mutations in tumor-derived cell lines and tumors. Nat Genet. 29:380-1.
Tobias ES, Hurlstone AF, MacKenzie E, McFarlane R, Black DM (2001) The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein. Oncogene. 20:2844-53.
Tobias ES, Patrick WJA, MacKenzie JR, Whiteford ML (2001) A case of Acro-renal-mandibular syndrome in an 18 week male fetus. Clin Dysmorphol. Jan;10(1):61-4.
Tobias ES, Bryce G, Farmer G, Barton J, Colgan J, Morrison N, Cooke A, Tolmie JL (2001) Absence of learning difficulties in a hyperactive boy with a terminal Xp deletion encompassing the MRX49 locus. J Med Genet. 38:466-70.
Bailey MES, Carter SA, Tobias ES, Kwan P, Sutton R, Sills GJ, Brodie MJ & Johnson KJ. (2001) Linkage and candidate gene analysis of idiopathic epilepsies. American Journal of Human Genetics 69: 1853
Tobias ES, Morrison N, Whiteford ML, Tolmie JL (1999) Towards earlier diagnosis of 22q11 deletions. Arch Dis Child. Dec;81(6):513-4.
Books
Tobias ES, Connor JM and Ferguson-Smith MA (2011) Essential Medical Genetics 6th edition. Wiley-Blackwell
Book Chapters
Tobias ES and Connor JM (2008) Genetic Counselling for childhood tumors and inherited cancer-predisposing syndromes. In The Surgery of Childhood Tumors, Second Edition. Eds R Carachi, AF Azmy and FJ Grosfeld. Heidelberg : Springer.
Tobias ES (2006). The Molecular Biology of Cancer. In Emery & Rimoin’s Principles & Practice of Medical Genetics, Fifth Edition. Edinburgh : Churchill Livingstone
Tobias ES (2002). Questions on Molecular Medicine & Genetics for the MRCP part 1. In Basic Science MRCP Question Book. Bodmin: MPG Books
Teaching
- Section Postgraduate Convenor for Medical Genetics
- External examiner for University of Aberdeen
- Provide three 3-hour Fixed Resource Sessions: all 3rd year MBChB students
- Intercalating BMedSci students: Cancer Studies module (lectures)
- Intercalating BMedSci students: Developmental Medicine module (lectures)
- Supervision of dissertations and laboratory projects of students on MSc Medical Genetics course
- Supervision of Lab projects for BMedSci course.
- Three lectures to students on the MSc Medical Genetics course
- Lectures on molecular medicine and clinical genetics for the MRCP examination
Research Opportunities
For further information of research opportunities within the group please contact Dr Tobias at the address above.
Collaborators
In addition to many colleagues in Medical Genetics, Glasgow:
Professor Faisal Ahmed, Yorkhill Hospital, Glasgow, UK.
Professor Adam Balen, Leeds Centre for Reproductive Medicine, UK
G-NETS team, Medical University of Gdansk, Poland
IMPACT team, Institute of Cancer Research, Royal Marsden Hospital, London, UK
Dr Helen Firth, Medical Genetics, Cambridge University, UK
Professor Rona MacKie, Dept. Public Health, 1 Lilybank Gardens, University of Glasgow, UK
Dr Jonathan Berg, Dept of Medical Genetics, University of Dundee, UK
Dr John Bartlett, Endocrine Cancer Group, Edinburgh Cancer Research Centre, UK
Dr Dilys Freeman, Division of Developmental Medicine, Glasgow Royal Infirmary, Glasgow, UK
Dr Fiona Douglas, Newcastle General Hospital, Newcastle, UK
Dr Heather Mefford, University of Washington School of Medicine, USA
Professor Sheila Unger, Dept of Human Genetics, University Hospital, Freiburg, Germany
Professor Andrea Superti-Furga, Dept of Pediatrics, University Hospital, Freiburg, Germany
Professor Meena Upadhyaya, Institute of Medical Genetics, Heath Park, Cardiff, UK
Professor Helene Dollfus, Service de Génétique Médicale, Hôpital de Hautpierre, Strasbourg, France
Professor Vincent Laugel, Laboratory of Medical Genetics, Strasbourg University Hospital, France
Professor Bernd Wollnik, Center for Molecular Medicine, University of Cologne, Germany.
Professor Veronica van Heyningen, MRC Human Genetics Unit, Western General Hospital , Edinburgh, UK