CAN WE PREDICT WHICH LEIOMYOSARCOMAS RECUR OR BORDERLINE TUMOURS WILL? FOR MOST CASES – YES, AND THERE MAY SOON BE A BLOOD TEST MARKER! W. Clow 1,2, T. Slatter3, P. Sykes4, C. Devenish1, J. Royds3, P Ip5, A. Cheung5, N. Hung1. 1 Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand 2 Department of Obstetrics & Gynaecology, Whakatane Hospital, Whakatane , New Zealand 3 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 4 Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand 5 Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Hong Kong SAR

Although leiomyosarcoma (LMS) is uncommon in gynaecological practice, patients generally have a poor prognosis. The 5 year survival rates are about 50%, but those patients who have recurrent disease often progress quickly, with serious recurrence and/or death within a few years1. Smooth muscle Tumours of Uncertain Malignant Potential (STUMP) have low mitotic counts, up to moderate cellular atypia and/or tumour necrosis. 10-27% recur as a leiomyosarcoma, with a similar pattern of poor outcome2. We have demonstrated that these poor outcome tumours malignant cellular immortality phenotype is the Alternative Lengthening of Telomeres (ALT3,4,5), a phenotype found in about 10% of all malignancies, and that the poor outcome ALT phenotype is particularly identified in LMS and STUMP tumours by its association with mutations of either or both of two demethylases - ATRX and DAXX (mutations which are implied by absence of immunochemical staining). Mutations of either or both of these demethylases identifies more aggressive tumours.

Figure 1 Examples of tumour staining for ATRX DAXX: Negative staining (right illustrations) indicates ATRX &/or DAXX mutation and is associated with recurrence and or death from the disease p=0.000. The FERN study is an international collaborative extension of that research project to a larger cohort to improve the statistical rigor of the study. It will test the usefulness of a blood test (C-circle assay6 - developed in Sydney) that identifies the ALT phenotype and may indicate its continuing activity or recurrence. The potential management value of the identification of ATRX and DAXX mutations commended to delegates and to encourage recruitment of patients to the study. Such a blood marker should have significant long term benefits in the early identification of recurrent disease, and monitoring disease regression, persistence or recurrence. The close correlation with outcomes of these findings may point to possible future chemotherapeutic advances. References (if permitted as extra words) References 1. Slatter TL, Hsia H, Samaranayaka A, Sykes P, Clow WM, Devenish CJ, Royds JA, Ip PPC, Cheung AN, Hung NA " Loss of ATRX and DAXX Expression Identifies Poor Progression for Uterine Smooth Muscle Tumors" The American Journal of Surgical Pathology - in press 2. Ip PP, Cheung AN, Clement PB. Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases. Am J Surg Pathol 2009;33:992-1005 3. Bryan TM, Englezou A, Dalla-Pozza L, et al. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 1997;3:1271-1274. 4. Hakin-Smith V, Jellinek DA, Levy D, et al. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 2003;361:836-838. 5. Henson JD, Hannay JA, McCarthy SW, et al. A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res 2005;11:217-225. 6. Henson JD, Cao Y, Huschtscha LI, Chang AC, Au AYM, Pickett HA & Reddel. DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat Biotec 2009;27:1181-6