Genetics and Cell Biology of Sarcoma
Group Leader: Professor Adrienne M Flanagan
This team studies the genetics and cell biology of sarcoma – tumours of bone and soft tissue.
Sarcomas are malignant tumours of the musculoskeletal system (bone and soft tissue) representing less than 2% of all cancers. However, the centralisation of the treatment of these tumours in the London Sarcoma Unit allows basic and clinical research to succeed. We have a large biobank of these rare tumours collected for over a decade which has allowed us play a central role in identifying the genetic alterations in these tumours.
The focus of the research is to refine the classification of bone and soft tissue tumours using molecular markers, and to identify biomarkers for prediction for both response to therapies, and clinical outcome.
We are currently going through a rapid phase of discovery whereby the genetic alterations in bone and soft tissue tumours are being catalogued. The next phase of the research will be to interrogate these genetic alterations. This will require the development of new models of disease in which the genetic alterations, alone and in combination, can be studied in order to determine their significance in terms of tumour growth and behavior, but also to determine how these induce resistance to conventional chemotherapy and new targeted treatments.
A rare locally aggressive malignant bone tumour, arises in the vertebral bodies, and shows notochordal differentiation. We have one of the largest chordoma tumour banks available for research purposes. We reported that this tumour expresses brachyury (Henderson et al., 2005;
Vujovic et al., 2006; Tirabosco et al. 2007), a crucial transcription factor, and have since shown that this transcription plays a central role in the disease (Pillay et al. 2012; Nelson et al. 2012).
We have generated 4 new chordoma cell lines which we are now screening against 1000 compounds to identify new therapies for this disease.
This is the second most common primary malignant bone tumour. We were the first to report that ~60% of these cancers have a mutation in the gene IDH1, and that this mutation is the cause of Ollier Disease and Maffucci syndrome. In collaboration with the Wellcome Trust Sanger Institute we have recently undertaken genome sequencing of ˜80 chondrosarcomas (manuscript in press).
The next phase of this research is to determine the significance of these genetic alterations both alone and in combination.
The most common primary malignant bone tumour is a disease that affects all ages but predominantly teenagers and adolescents. It is a heterogeneous disease, both morphologically and genetically. Conventional chemotherapy was introduced as part of treatment for this disease in the 19080 when it dramatically improved outcome to approximately 60% survival over 5 years. However, there has been little advance made since that time.
A large number of our tumours is currently undergoing genomic sequencing in the Wellcome Trust Sanger Institute as part of the International Cancer Genome Consortium and it is hoped that this will provide insight into this complex disease and allow the development of new treatments.
Nerve sheath tumours
Nerve sheath tumours arise from the cells around nerves. Benign nerve sheath tumours (schwannomas and neurofibromas) and malignant (malignant peripheral nerve sheath tumours – MPNST) occur rarely in the general population and commonly in individuals with
a disease known as neurofibromatosis type 1. This project is working towards identifying a molecular signature which could distinguish easily between benign and malignant nerve sheath tumours and identifying therapeutic targets for the treatment of malignant disease (Parrinello S et al., 2008; Presneau 2012). We are collaborating with Stefan Beck, Professor of Medical Genomics, in the study of methylation of nerve sheath tumours.
Frequent mutation of the major cartilage collagen gene, COL2A1, in chondrosarcoma.
Patrick S Tarpey PS, Behjati S, Susanna Cooke S, Van Loo P, Wedge DC, Pillay N, John Marshall J, O’Meara S, Davies H, Nik-Zainal S, Beare D, Butler A, Gamble J, Hardy C, Hinton C, Jia MM, Jayakumar A, Jones, D, Latimer C, Maddison M, Martin S, McLaren S, Menzies A, Mudie L, Raine K, Teague JW, Tubio J, Halai D, Tirabosco R, Amary F, Campbell PJ, Stratton M, Flanagan AM, Futreal AM. In press Nature Genetics 2013
A common single-nucleotide variant in T is strongly associated with chordoma.
Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, Halai D, Berisha F, Cannon SR, Mead S, Kasperaviciute D, Palmen J, Talmud PJ, Kindblom LG, Amary MF, Tirabosco R, Flanagan AM. Nat Genet. 2012 Nov;44(11):1185-7. doi: 10.1038/ng.2419.
Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.
Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM. Nat Genet. 2011 Nov 6;43(12):1262-5. doi: 10.1038/ng.994.
An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma.
Nelson AC, Pillay N, Henderson S, Presneau N, Tirabosco R, Halai D, Berisha F, Flicek P, Stemple DL, Stern CD, Wardle FC, Flanagan AM. J Pathol. 2012 Nov;228(3):274-85. doi: 10.1002/path.4082.
IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.
Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM. J Pathol. 2011 Jul;224(3):334-43. doi: 10.1002/path.2913.
MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression.
Presneau N, Eskandarpour M, Shemais T, Henderson S, Halai D, Tirabosco R, Flanagan AM. Br J Cancer. 2013 Mar 5;108(4):964-72. doi: 10.1038/bjc.2012.518.
Professor Adrienne M Flanagan
+44 (0)20 7679 6304
Research Active Clincial Staff
Dr M Fernanda Amary FRCPath PhD – RNOH, consultant pathologist, honorary senior lecturer, UCL
Dr Roberto Tirabosco FRCPath - RNOH Consultant Pathologist
Dr Nischalan Pillay FRCPath PhD - Clinical Research Associate
Scientific Research Staff
Dr Nadege Presneau PhD - Senior Research Associate
Dr Diana Carvalho PhD - Postdoctoral scientist
Dr Lucia Cottone PhD - Postdoctoral scientist
- Mette Jorgensen - PhD student
- Tarek Shamais - PhD student
- Susanne Scheipl - Clinical Fellow
Collaborators and Partnerships
- The London Sarcoma Service, the largest sarcoma service in the UK delivered from at The Royal National Orthopaedic Hospital, and University College London Hospital
- Wellcome Trust Sanger Institute Cancer Genome Project Group
- Professor Amit Nathwani of the UCL Cancer Institute
- Professor Alison Lloyd, MRC laboratory for molecular cell biology