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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 - PowerPoint PPT Presentation
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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 LMS CS ESS US
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 6/6 3/4
Soslow, 2008 6/7
sarcoma myoma myometrium0
1
2
3
IHC expression WT1
inte
nsity
Materials and methods (1)
54 women with high grade uterine sarcoma Follow up of at least 12 months
No. of patients
n (%)
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 14 (26)
US 7 (13) Yes 40 (74)
Stage Death
I 22 (41) No 18 (33)
II 6 (11) Yes 36 (67)
III 12 (22)
IV 14 (26)
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)
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) 4 (20) Recurrent disease
CS 14 (41) 13 (65) No 6 (18) 12 (60)
US 4 (12) 3 (15) Yes 28 (82) 8 (40)
Stage Death
I 10 (29) 12 (60) No 7 (21) 9 (45)
II-IV 24 (71) 8 (40) Yes 27 (79) 11 (55)
Results (2) : univariate analysis
Kaplan Meier survival curves
Results (3) : univariate analysis
OS
0 50 100 150 200 2500.00.10.20.30.40.50.60.70.80.91.01.1
WT1 -WT1 +WT1 +++
MONTHS
Fra
ctio
n s
urv
ival
PFS
0 50 100 150 200 2500.00.10.20.30.40.50.60.70.80.91.01.1
WT1 -WT1 +WT1 +++
MONTHS
Fra
ctio
n s
urv
ival
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 0.147-1.6090.442
LMS vs US 0.743 0.255-2.166
Size 1.775 0.484-6.517 0.385
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 0.075-0.9800.100
LMS vs US 0.325 0.104-1.014
Size 1.493 0.368-6.054 0.572
PFS
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)