Genetics and Cell Biology of Sarcoma

Sarcomas

Sarcomas are malignant tumours of the musculoskeletal system (bone and soft tissue) representing less than 2% of all cancers. However, the centralisation of treatment of patients with these tumours in the London Sarcoma Unit allows basic and clinical research to succeed. This gave us the opportunity to biobank these rare tumours and over the last decade, we have contributed to the refinement of the classification of primary bone tumours through the discovery of new genetic alterations which define specific tumour types.

Now, we are exploiting the molecular profiles of these tumours in two ways:

• by developing biomarkers and employing them as clinical tests to provide patients with more accurate prognoses and to predict if tumours are sensitive to conventional chemotherapy and new targeted treatments.
• by interrogating the tumours by applying state of the art technology using in vitro models of disease to study the genetic alterations, alone and in combination, to determine their significance in terms of tumour growth and behaviour, but also to determine how these induce resistance to conventional chemotherapy and new targeted treatments. 

Sarcoma and the 100,000 Genomes Project

The 100,000 Genomes Project has demonstrated that genomics can play a pivotal role in improving diagnosis and treatment for patients with sarcoma. At least 1,000 patients with sarcoma have been recruited to the 100,000 Genomes Project, 600 of whom were recruited at the Royal National Orthopaedic Hospital as part of the London Sarcoma Service.  

Already we have seen changes in practice in pathology laboratories as a result of this project. Preliminary analysis of the genomes shows that more accurate diagnoses can be provided, and patients with germline alterations can be identified more readily. Best of all, this project has resulted in a more collaborative and comprehensive research strategy for this rare disease.

As of early 2020, all sarcomas or tumours suspected of being sarcoma can be submitted to NHS England for whole Genome Sequencing and these genomes can be added to the profiles of tumours being analysed as part of the 100,000 Genomes Project.

Sarcoma represents no more than 2% of all cancers but due to the commitment of NHS staff across the Genome Medical Centres, the numbers of sarcoma genomes analysed are greater than all cancers except breast and colorectal.

Key publications

1. Amary MF, Damato S, Halai D ... Flanagan AM (2011). Ollier disease and Maffuci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. Nov 6;43(12): 1262-5. 
2. Pillay N, Plagnol V, Tarpey PS ... Flanagan AM (2012). A common single nucleotide variant in T is strongly associated with chordoma. Nat Genet. Nov;44(11): 1185-7. 
3. Nelson AC, Pillay N, Henderson S ... Flanagan AM (2012). An integrated functional genomics approach identifies the regulatory network directed by brachyury in chordoma. J Pathol. Nov;228(3): 274-85. 
4. Patrick S Tarpey PS, Behjati S ... Flanagan AM, Futreal AM (2013). Frequent mutation of the major cartilage collagen gene, COL2A1, in chondrosarcoma. Nat Genet. Aug;45(8): 923-6. 
5. Behjati S, Tarpey PS, Presneau N ... Flanagan AM (2013). Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. Dec; 45(12): 1479-82. 
6. Amary M, Ye H, Berisha F, Khatri B ... Flanagan AM (2016). EGFR inhibitors Identified as a Potential Treatment for Chordoma in a Focused Compound Screen. J Pathol. Apr 22;239(3): 320-334.
7. Tarpey P, Behjati S, Young MD ... Flanagan AM, Campbell PJ (2017). The driver landscape of sporadic chordoma. Nature Commun. 8(890): 1-11. 
8. Behjati S, Tarpey P, Haase K ... Flanagan AM, Campbell PJ (2017). Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nature Commun. 8(15936): 1-8.
9. Fittall M, Mifsud W, Pillay, N, Ye H ... Flanagan AM, Behjati, S (2018). Recurrent rearrangements of FOS and FOSB define osteoblastoma. Nature Communications 9(1)2150: 1-6. 
10. Steele CD, Tarabichi M, Oukrif D ... Flanagan AM, Pillay N (2019). Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways. Cancer Cell. Mar 18;35(3): 441-456.e8. 
11. Baumhoer D, Kovac M, Sperveslage J ... Flanagan AM, Hartmann W (2018). Activating mutations in the MAP-kinase pathway define non-ossifying fibroma of bone. J Pathol. 2019 May;248(1): 116-122. 
12. Amary MF, Perez-Casanova L, Ye H ... Flanagan AM (2019). Synovial chondromatosis and soft tissue chondroma: extra-osseous cartilaginous tumours defined by FN1 gene rearrangement. Mod Pathol. 2019 Jul 4.