IGF2BP3 (IMP3) Expression Is a Marker of Unfavorable Prognosis in Ovarian Carcinoma of Clear Cell Subtype

Martin Köbel; Haodong Xu; Patricia A. Bourne; Betsy O. Spaulding; Ie-Ming Shih; Tsui-Lien Mao; Robert A. Soslow; Carol A. Ewanowich; Steve E. Kalloger; Erika Mehl; Cheng-Han Lee; David Huntsman; C. Blake Gilks

Disclosures

Mod Pathol. 2009;22(3):469-475. 

In This Article

Results

IGF2BP3 expression by immunohistochemistry correlated strongly with mRNA levels in a set of 35 ovarian carcinomas (Figure 1, r = 0.849, P < 0.001). IGF2BP3 staining was not observed in sections of normal tissue, including ovarian stroma and surface epithelium, fallopian tube, and endometrium (data not shown).

Figure 1.

Relative amount of IGF2BP3 mRNA for immunohistochemically IGF2BP3-negative and -positive ovarian carcinomas.

Forty-seven percent of ovarian carcinomas of the British Columbia cohort showed IGF2BP3 expression (Figure 2, all slides are available online at http://bliss.gpec.ubc.ca/ (under OOU)). IGF2BP3 expression differed between subtypes (P < 0.001, Pearson's chi-square, Table 1 ). The highest rate of expression was seen in the mucinous subtypes (86%, N = 30), followed by clear cell carcinomas (52%, N = 128) and high-grade serous carcinomas (50%, N = 198), with the lowest expression rate in endometrioid subtype (27%, N = 121). Disease-specific survival was found to be significantly shorter in patients with IGF2BP3 expressing clear cell carcinomas (P = 0.001, Figure 3a). There was no significant difference in disease-specific survival between patients whose tumors did and those whose tumors did not express IGF2BP3 for high-grade serous (Figure 3b) or endometrioid subtypes (Figure 3c). In clear cell carcinoma only stage was a significant clinical risk factor in univariate analysis (data not shown) and therefore was introduced into a multivariable Cox proportional hazards regression model, together with IGF2BP3 status. For IGF2BP3 expression, a risk ratio of 2.9 (95% confidence interval 1.4–5.8, Table 2 ) independent from stage was calculated.

Figure 2.

Immunohistochemical stains for IGF2BP3 showing a tissue microarray consisting of ovarian clear cell carcinomas of the validation set. Lower left-a clear cell carcinoma negative for IGF2BP3, lower right-a clear cell carcinoma positive for IGF2BP3.

Figure 3.

Kaplan–Meier analysis of disease-specific survival in ovarian carcinomas: (a) ovarian clear carcinomas from British Columbia (N=128), (b) ovarian high-grade serous carcinomas (N=198), (c) ovarian endometrioid carcinomas (N=121), and (d) ovarian clear cell carcinomas from the validation set (N=150). P-values were calculated using the log-rank test.

To validate this finding, an independent cohort of 150 ovarian clear cell carcinomas from three other centers (N = 69 from Johns Hopkins University, Baltimore, MD, USA, N = 42 from University of Alberta, Edmonton, Canada, and N = 39 from Memorial Sloan Cancer Center, New York, NY, USA) was assessed for IGF2BP3 expression. The IGF2BP3 expression rate was similar to the BC cohort, with 54.0 and 51.6% of clear cell carcinomas showing IGF2BP3 expression, respectively. Univariate and multivariate analyses confirmed the independent prognostic significance of IGF2BP3 expression for ovarian clear cell carcinoma in this series (Figure 3d and Table 2 ).

On the basis of these findings, we combined both series and calculated the risk ratio for ovarian clear cell carcinomas in stage I or II based on IGF2BP3 expression. Patients with IGF2BP3-expressing tumors exhibited a risk ratio of 2.8 (95% confidence interval, 1.6–5.1) for disease-specific survival. The 5-year disease-specific survival rate for women with IGF2BP3-negative ovarian clear cell carcinoma in stage I or II was 88% (standard error 3.5%) and for IGF2BP3-positive tumors was 67% (standard error 4.9%).

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