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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

Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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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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Page 1: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 2: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 3: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 4: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 5: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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)

Page 6: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 7: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 8: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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)

Page 9: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

Results (2) : univariate analysis

Kaplan Meier survival curves

Page 10: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 11: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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

Page 12: Wilms’ tumour gene 1 (WT1) is a new prognostic marker in high grade uterine sarcoma

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)