Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma A. Coosemans, B. Van Calster, L. Verbist, Ph. Moerman, I. Vergote,

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Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma A. Coosemans, B. Van Calster, L. Verbist, Ph. Moerman, I. Vergote, S.W. Van Gool, F. Amant Laboratory of Experimental Gynaecology and Immunology, UZ Gasthuisberg, Katholieke Universiteit Leuven, Belgium Department of Electric Engineering (ESAT), Katholieke Universiteit Leuven, Belgium Department of human pathology, UZ Gasthuisberg, Katholieke Universiteit Leuven, Belgium

Background (1) WT1 : Wilms’ tumour gene 1 located on #11p13 1990 : discovered in Wilms tumour (paediatric kidney cancer) Complex molecular function : transcription and translation on DNA and RNA level Role : Embryogenic : role in development of urogenital system, central nervous system, heart, blood Adult life : role in carcinogenesis – overexpression of wild type in several haematological and solid malignancies Depending on the type of tumour : behaviour as a oncogene or supressor gene

Background (2) Uterine sarcoma : Rare type of uterine tumour 4 subtypes : Carcinosarcoma (CS), leiomyosarcoma (LMS), undifferentiated sarcoma (US) : high grade Endometrial stromal sarcoma (ESS) : low grade Poor prognosis : 5 year survival : Stage I-II : 50% Stage III-IV : 10% Surgery is the corner stone - no clear benefits from adjuvant therapy in early stages – shortlasting therapeutic options in advanced stages

Background (3) WT1 and uterine sarcoma IHC RT-PCR CS ESS LMS US AS Agoff, 2001 9/10 Dupont, 2004 7/10 Sumathi, 2004 13/14 Sotobori, 2006 5/5 Coosemans, 2007 12/27 7/15 29/38 4/7 6/6 4/4 3/4 Soslow, 2008 6/7

Materials and methods (1) 54 women with high grade uterine sarcoma Follow up of at least 12 months No. of patients n (%) Age Tumoural size <52 yrs 10 (18,5) <5cm 8 (15) ≥ 52 yrs 44 (81,5) ≥5cm 32 (59) Sarcoma subtype unknown 14 (26) LMS 20 (37) Recurrent disease CS 27 (50) No US 7 (13) Yes 40 (74) Stage Death I 22 (41) 18 (33) II 6 (11) 36 (67) III 12 (22) IV

Materials and methods (2) IMMUNOHISTOCHEMISTRY WT1 immunohistochemistry on 1 slide of each tumour (monoclonal mouse anti-human Wilms’ Tumor 1 clone 6F-H2 (DAKO)) STATISTICAL ANALYSIS Survival curves by Kaplan Meier Univariate and multivariate analysis by Cox regression analysis

Materials and methods (3) 1984-2008 : 26 studies on prognosis in uterine sarcoma, including multivariate analysis in more than 40 patients Most frequently studied parameters : Stage : 24 studies Age : 23 studies Grade : 15 studies Subtype : 11 studies Menopauzal status : 10 studies Size : 9 studies Mitotic index : 8 studies Adjuvant therapy : 6 studies

Results (1) WT1 positive tumors 34 (63) WT1 negative tumors 20 (37) Age Tumoral size <52 yrs 6 (18) 4 (20) <5cm 5 (15) 3 (15) ≥ 52 yrs 28 (82) 16 (80) ≥5cm 22 (65) 10 (50) Sarcoma subtype unknown 7 (21) 7 (35) LMS 16 (47) Recurrent disease CS 14 (41) 13 (65) No 12 (60) US 4 (12) Yes 8 (40) Stage Death I 10 (29) 9 (45) II-IV 24 (71) 27 (79) 11 (55)

Results (2) : univariate analysis Kaplan Meier survival curves

Results (3) : univariate analysis LR p=0,0058 LR p <0,0001

Results (4) : multivariate analysis Variable Hazard ratio 95% CI on HR LR P-value WT1 status 2.381 1.151-4.926 0.019 Stage 2.953 1.294-6.739 0.010 Age 1.053 0.775-1.430 0.742 Sarcoma subtype CS vs US 0.486 0.147-1.609 0.442 LMS vs US 0.743 0.255-2.166 Size 1.775 0.484-6.517 0.385 PFS Variable Hazard ratio 95% CI on HR LR P-value WT1 status 2.990 1.286-6.950 0.011 Stage 4.995 1.882-13.26 0.001 Age 1.194 0.845-1.687 0.315 Sarcoma subtype CS vs US 0.272 0.075-0.980 0.100 LMS vs US 0.325 0.104-1.014 Size 1.493 0.368-6.054 0.572 OS

Conclusion WT1 independently worsens the prognosis of uterine sarcoma The stronger the WT1 expression, the worse the prognosis Similar observations have been made in breast carcinoma (Miyoshi, 2002), leukaemia (Inoue, 1994) and hepatocellular carcinoma (Sera, 2008)