Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas

David S P Tan; Marjan Iravani; W Glenn McCluggage; Maryou B K Lambros; Fernanda Milanezi; Alan Mackay; Charles Gourley; Felipe C Geyer; Radost Vatcheva; Joanne Millar; Karen Thomas; Rachael Natrajan; Kay Savage; Kerry Fenwick; Alistair Williams; Charles Jameson; Mona El-Bahrawy; Martin E Gore; Hani Gabra; Stanley B Kaye; Alan Ashworth; Jorge S Reis-Filho

doi:10.1158/1078-0432.CCR-10-1688

Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas

David S P Tan, Marjan Iravani, W Glenn McCluggage, Maryou B K Lambros, Fernanda Milanezi, Alan Mackay, Charles Gourley, Felipe C Geyer, Radost Vatcheva, Joanne Millar, Karen Thomas, Rachael Natrajan, Kay Savage, Kerry Fenwick, Alistair Williams, Charles Jameson, Mona El-Bahrawy, Martin E Gore, Hani Gabra, Stanley B KayeAlan Ashworth, Jorge S Reis-Filho

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist.

Experimental design: Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test.

Results: Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors.

Conclusions: OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs. Clin Cancer Res; 17(6); 1521-34. (C) 2011 AACR.

Original language	English
Pages (from-to)	1521-1534
Number of pages	14
Journal	Clinical Cancer Research
Volume	17
Issue number	6
DOIs	https://doi.org/10.1158/1078-0432.CCR-10-1688
Publication status	Published - 15 Mar 2011

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10.1158/1078-0432.CCR-10-1688

http://clincancerres.aacrjournals.org/content/17/6/1521

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Tan, D. S. P., Iravani, M., McCluggage, W. G., Lambros, M. B. K., Milanezi, F., Mackay, A., Gourley, C., Geyer, F. C., Vatcheva, R., Millar, J., Thomas, K., Natrajan, R., Savage, K., Fenwick, K., Williams, A., Jameson, C., El-Bahrawy, M., Gore, M. E., Gabra, H., ... Reis-Filho, J. S. (2011). Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas. Clinical Cancer Research, 17(6), 1521-1534. https://doi.org/10.1158/1078-0432.CCR-10-1688

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title = "Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas",

abstract = "Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist.Experimental design: Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test.Results: Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors.Conclusions: OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs. Clin Cancer Res; 17(6); 1521-34. (C) 2011 AACR.",

author = "Tan, {David S P} and Marjan Iravani and McCluggage, {W Glenn} and Lambros, {Maryou B K} and Fernanda Milanezi and Alan Mackay and Charles Gourley and Geyer, {Felipe C} and Radost Vatcheva and Joanne Millar and Karen Thomas and Rachael Natrajan and Kay Savage and Kerry Fenwick and Alistair Williams and Charles Jameson and Mona El-Bahrawy and Gore, {Martin E} and Hani Gabra and Kaye, {Stanley B} and Alan Ashworth and Reis-Filho, {Jorge S}",

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doi = "10.1158/1078-0432.CCR-10-1688",

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Tan, DSP, Iravani, M, McCluggage, WG, Lambros, MBK, Milanezi, F, Mackay, A, Gourley, C, Geyer, FC, Vatcheva, R, Millar, J, Thomas, K, Natrajan, R, Savage, K, Fenwick, K, Williams, A, Jameson, C, El-Bahrawy, M, Gore, ME, Gabra, H, Kaye, SB, Ashworth, A & Reis-Filho, JS 2011, 'Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas', Clinical Cancer Research, vol. 17, no. 6, pp. 1521-1534. https://doi.org/10.1158/1078-0432.CCR-10-1688

TY - JOUR

T1 - Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas

AU - Tan, David S P

AU - Iravani, Marjan

AU - McCluggage, W Glenn

AU - Lambros, Maryou B K

AU - Milanezi, Fernanda

AU - Mackay, Alan

AU - Gourley, Charles

AU - Geyer, Felipe C

AU - Vatcheva, Radost

AU - Millar, Joanne

AU - Thomas, Karen

AU - Natrajan, Rachael

AU - Savage, Kay

AU - Fenwick, Kerry

AU - Williams, Alistair

AU - Jameson, Charles

AU - El-Bahrawy, Mona

AU - Gore, Martin E

AU - Gabra, Hani

AU - Kaye, Stanley B

AU - Ashworth, Alan

AU - Reis-Filho, Jorge S

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist.Experimental design: Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test.Results: Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors.Conclusions: OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs. Clin Cancer Res; 17(6); 1521-34. (C) 2011 AACR.

AB - Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist.Experimental design: Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test.Results: Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors.Conclusions: OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs. Clin Cancer Res; 17(6); 1521-34. (C) 2011 AACR.

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U2 - 10.1158/1078-0432.CCR-10-1688

DO - 10.1158/1078-0432.CCR-10-1688

M3 - Article

C2 - 21411445

VL - 17

SP - 1521

EP - 1534

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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ER -

Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas

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