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Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry.

Kim BW, Cho H, Chung JY, Conway C, Ylaya K, Kim JH, Hewitt SM - J Transl Med (2013)

Bottom Line: Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference.After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tissue Array Research Program & Applied Molecular Pathology Lab, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT

Background: Hypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.

Methods: The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated.

Results: HIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.

Conclusions: We demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

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Kaplan-Meier plots of disease-free survival (A - D) and overall survival (E – H) for categorized by HIF-1α (A &E), c-Met (B &F), CA9 (C &G) and GLUT1 (D &H). High HIF-1α expression shows worse disease-free survival (A, P = 0.002) and overall survival rate (E, P = 0.047) than low expression (P = 0.047). Patients with high c-Met expression displayed shorter disease-free (P = 0.035) and overall survival (P = 0.005) compared with that of patients with low c-Met expression (B &F). P values for two-sided log-rank statistics are given for each plot. Cut-off value of HIF-1α, c-Met, CA9 and GLUT1 are 8, 8, 2 and 8 of IHC score, respectively.
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Figure 3: Kaplan-Meier plots of disease-free survival (A - D) and overall survival (E – H) for categorized by HIF-1α (A &E), c-Met (B &F), CA9 (C &G) and GLUT1 (D &H). High HIF-1α expression shows worse disease-free survival (A, P = 0.002) and overall survival rate (E, P = 0.047) than low expression (P = 0.047). Patients with high c-Met expression displayed shorter disease-free (P = 0.035) and overall survival (P = 0.005) compared with that of patients with low c-Met expression (B &F). P values for two-sided log-rank statistics are given for each plot. Cut-off value of HIF-1α, c-Met, CA9 and GLUT1 are 8, 8, 2 and 8 of IHC score, respectively.

Mentions: Five year disease-free survival and overall survival were analyzed through the Kaplan-Meier plots as shown in Figure 3. In survival analysis of HIF-1α, there were 20 recurrences and 11 deaths in 60 high expression patients, while 11 recurrences and 6 deaths in 91 low expression patients were shown during 5 year follow-up period. Mean 5-year overall survival time was 56.9 and 51.9 months in low HIF-1α expressions and high HIF-1α expressions, respectively. High expression of HIF-1α showed worse disease-free survival and overall survival rate than those of low expression group (P = 0.002 and P = 0.047, respectively) (Figure 3A & E). In survival analysis with c-Met expression, 13 recurrences and 10 deaths in 42 c-Met high expressions occurred, while 18 recurrences and 7 deaths were observed in 110 low expressions. Mean 5-year overall survival time was 56.5 months in low c-Met expression and 50.8 months in high c-Met expression. High expression of c-Met showed poorer disease-free and overall survival rate than low expression group with significant difference (P = 0.035 and P = 0.005, respectively) (Figure 3B & F). However, CA9 and GLUT1 did not show significant difference of disease-free survival (Figure 3C and D) and overall survival (Figure 4G & H) between high and low expression. When survival of patients with expression of high HIF-1α/high c-Met was compared with that of those with low HIF-1α/low c-Met, Kaplan-Meier analysis revealed a significant difference on both disease-free survival (P = 0.003, Figure 4A) and overall survival (P = 0.003, Figure 4B).


Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry.

Kim BW, Cho H, Chung JY, Conway C, Ylaya K, Kim JH, Hewitt SM - J Transl Med (2013)

Kaplan-Meier plots of disease-free survival (A - D) and overall survival (E – H) for categorized by HIF-1α (A &E), c-Met (B &F), CA9 (C &G) and GLUT1 (D &H). High HIF-1α expression shows worse disease-free survival (A, P = 0.002) and overall survival rate (E, P = 0.047) than low expression (P = 0.047). Patients with high c-Met expression displayed shorter disease-free (P = 0.035) and overall survival (P = 0.005) compared with that of patients with low c-Met expression (B &F). P values for two-sided log-rank statistics are given for each plot. Cut-off value of HIF-1α, c-Met, CA9 and GLUT1 are 8, 8, 2 and 8 of IHC score, respectively.
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Related In: Results  -  Collection

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Figure 3: Kaplan-Meier plots of disease-free survival (A - D) and overall survival (E – H) for categorized by HIF-1α (A &E), c-Met (B &F), CA9 (C &G) and GLUT1 (D &H). High HIF-1α expression shows worse disease-free survival (A, P = 0.002) and overall survival rate (E, P = 0.047) than low expression (P = 0.047). Patients with high c-Met expression displayed shorter disease-free (P = 0.035) and overall survival (P = 0.005) compared with that of patients with low c-Met expression (B &F). P values for two-sided log-rank statistics are given for each plot. Cut-off value of HIF-1α, c-Met, CA9 and GLUT1 are 8, 8, 2 and 8 of IHC score, respectively.
Mentions: Five year disease-free survival and overall survival were analyzed through the Kaplan-Meier plots as shown in Figure 3. In survival analysis of HIF-1α, there were 20 recurrences and 11 deaths in 60 high expression patients, while 11 recurrences and 6 deaths in 91 low expression patients were shown during 5 year follow-up period. Mean 5-year overall survival time was 56.9 and 51.9 months in low HIF-1α expressions and high HIF-1α expressions, respectively. High expression of HIF-1α showed worse disease-free survival and overall survival rate than those of low expression group (P = 0.002 and P = 0.047, respectively) (Figure 3A & E). In survival analysis with c-Met expression, 13 recurrences and 10 deaths in 42 c-Met high expressions occurred, while 18 recurrences and 7 deaths were observed in 110 low expressions. Mean 5-year overall survival time was 56.5 months in low c-Met expression and 50.8 months in high c-Met expression. High expression of c-Met showed poorer disease-free and overall survival rate than low expression group with significant difference (P = 0.035 and P = 0.005, respectively) (Figure 3B & F). However, CA9 and GLUT1 did not show significant difference of disease-free survival (Figure 3C and D) and overall survival (Figure 4G & H) between high and low expression. When survival of patients with expression of high HIF-1α/high c-Met was compared with that of those with low HIF-1α/low c-Met, Kaplan-Meier analysis revealed a significant difference on both disease-free survival (P = 0.003, Figure 4A) and overall survival (P = 0.003, Figure 4B).

Bottom Line: Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference.After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tissue Array Research Program & Applied Molecular Pathology Lab, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT

Background: Hypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.

Methods: The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated.

Results: HIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.

Conclusions: We demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

Show MeSH
Related in: MedlinePlus