IMP3 Expression and Unfavorable Prognosis in Ovarian Carcinoma

In This Article

Abstract and Introduction

Abstract

Clear cell carcinoma is an uncommon subtype of ovarian carcinoma, accounting for 10% of cases. Clear cell carcinoma typically presents with stage I or II disease, and in this setting prognostic markers could aid in management decisions, in particular the decision to treat with adjuvant chemotherapy. We tested whether expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3, also known as IMP3) can serve as a new biomarker to predict outcome for patients with clear cell carcinoma and other subtypes of ovarian carcinoma. The expression of IGF2BP3 was evaluated by immunohistochemistry in 475 ovarian carcinomas of different subtypes and correlated with disease-specific survival. IGF2BP3 antibody specificity was validated by correlation of IGF2BP3 protein with mRNA expression level in a series of 35 ovarian carcinomas (r = 0.849, P < 0.0001). IGF2BP3 protein expression was an independent marker of reduced disease-specific survival (risk ratio 2.9, 95% confidence interval 1.4–5.8) in the clear cell subtype (N = 128), but not in high-grade serous (N = 198) or endometrioid (N = 121) carcinomas. The prognostic significance of IGF2BP3 expression for reduced disease-specific survival (risk ratio 2.6, 95% confidence interval 1.3–5.0) was confirmed in an independent series of cases (N = 150) from three different centers in North America. We conclude that IGF2BP3 is the first biomarker of prognostic significance in ovarian clear cell carcinoma that has been validated in an independent case series.

Introduction

The insulin-like growth factor mRNA-binding protein family comprises three proteins (IGF2BP1–3), which regulate mRNA transport, translation, and turnover by binding the coding regions of target mRNAs such as IGF2 (insulin-like growth factor 2), MYC, and ACTB (β-actin).^[1,2,3,4] IGF2BP expression is almost exclusively restricted to embryogenesis, with little or no detectable protein in normal adult tissues.^[5] We have recently shown that IGF2BP1 (alias IMP1) is overexpressed in high-grade ovarian carcinomas of serous and clear cell subtypes.^[6] Another family member, IGF2BP3, was cloned from a pancreatic tumor cDNA screen and was originally designated as KOC (KH-domain-containing protein overexpressed in cancer).^[7] IGF2BP3 expression has been associated with an unfavorable outcome in renal clear cell carcinoma.^[8,9] On the basis of this finding, we postulated that IGF2BP3 expression could also be a prognostic indicator for ovarian clear cell carcinoma, a tumor type with morphologic similarities to renal clear cell carcinoma.

Together with endometrioid carcinomas, clear cell carcinomas are the second most common subtype of ovarian carcinomas after high-grade serous subtype. They account for 10% of all cases, and are mostly (80%) diagnosed at stage I or II.^[10,11] Women diagnosed with ovarian clear cell carcinomas have a 5-year overall survival ranging from 88% in stage I to 33% in stage III.^[12] Except for stage, there are no validated prognostic factors for clear cell carcinoma and their behavior is unpredictable and in some cases follow an aggressive clinical course. Histopathological grading, for example, is not used as it has consistently been shown to be of no prognostic significance;^[11] as such all clear cell carcinomas are considered to be grade III.^[13] In the absence of validated prognostic factors for clear cell carcinoma, we sought to determine whether expression of IGF2BP3 correlates with prognosis for this distinct subtype.

Cite this: IGF2BP3 (IMP3) Expression Is a Marker of Unfavorable Prognosis in Ovarian Carcinoma of Clear Cell Subtype - Medscape - Mar 01, 2009.

Table 1. Clinicopathological Characteristics and IGF2BP3 Expression of Patients With Ovarian Carcinomas
Cohort by subtype	N	Age (mean±s.d.)	Stage III/IV (%)	IBP2BP3 expression (%)
British Columbia cohort	475	57.9±12.8	16.8	46.8
High-grade serous	196	60.8±11.5	33.2	50.0
Clear cell	128	56.4±13.3	7.0	51.6
Endometrioid	121	55.5±13.2	4.1	27.3
Mucinous	30	55.6±13.7	3.3	86.7
Validation set
Clear cell	150	51.5±10.8	23.7	54.0

s.d. = standard deviation.

Table 1. Clinicopathological Characteristics and IGF2BP3 Expression of Patients With Ovarian Carcinomas
Cohort by subtype	N	Age (mean±s.d.)	Stage III/IV (%)	IBP2BP3 expression (%)
British Columbia cohort	475	57.9±12.8	16.8	46.8
High-grade serous	196	60.8±11.5	33.2	50.0
Clear cell	128	56.4±13.3	7.0	51.6
Endometrioid	121	55.5±13.2	4.1	27.3
Mucinous	30	55.6±13.7	3.3	86.7
Validation set
Clear cell	150	51.5±10.8	23.7	54.0

s.d. = standard deviation.

Table 2. Multivariable Analysis for Disease-specific Survival of the Ovarian clear cell carcinomas
Variable	British Columbia cohort		Validation set
Variable	RR (95% CI)	P-value	RR (95% CI)	P-value
Stage (III/IV vs I/II)	3.7 (1.5–8.8)	0.004	7.4 (4.0–13.6)	< 0.001
IGF2BP3 Expression (+ vs -)	2.9 (1.4–5.8)	0.003	2.6 (1.3–5.0)	0.006

CI = confidence interval; RR = risk ratio.

Table 2. Multivariable Analysis for Disease-specific Survival of the Ovarian clear cell carcinomas
Variable	British Columbia cohort		Validation set
Variable	RR (95% CI)	P-value	RR (95% CI)	P-value
Stage (III/IV vs I/II)	3.7 (1.5–8.8)	0.004	7.4 (4.0–13.6)	< 0.001
IGF2BP3 Expression (+ vs -)	2.9 (1.4–5.8)	0.003	2.6 (1.3–5.0)	0.006

CI = confidence interval; RR = risk ratio.

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