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  • Original Paper
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Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential

Oncogene volume 24, pages 1053–1065 (2005)Cite this article

Abstract

Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12 500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2–G3 groups of tumors was highly correlated to patient outcome (χ2 for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular ‘meta-signature’ in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

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Acknowledgements

We thank Doris Karow (CGH), Herta Bettendorf and Kathrin Richter (immunohistochemistry), Dr Dominique Könsgen and Dr Alexander Mustea (acquisition of tumor material and clinical data of Berlin cases) and Professor Dr Gerald Gitsch (providing access to outcome data associated with the cases obtained at Freiburg). This work was supported in part by the Deutsche Krebshilfe/German Cancer Aid (Grants # 70-3099-Me 1 and 70-1970-Ki 2 and D/98/02291 to IMH).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, Kiel, Germany

    Ivo Meinhold-Heerlein, Dirk Bauerschlag, Felix Hilpert, Walter Jonat, Anja Jacobsen & Norbert Arnold

  2. Cancer Biology Discovery, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA

    Dirk Bauerschlag, Petre Dimitrov, Lisa M Sapinoso & Garret M Hampton

  3. Department of Pathology, University of Freiburg, Germany

    Marzenna Orlowska-Volk

  4. Lilly Deutschland, Bad Homburg, Germany

    Thomas Bauknecht

  5. Department of Gynecology and Obstetrics, University of Bonn, Germany

    Tjoung-Won Park

  6. Department of Gynecology and Obstetrics, University Hospital Charite, Berlin, Germany

    Jalid Sehouli

  7. Department of Pathology, University of Kiel, Germany

    Jutta Luttges

  8. Burnham Institute, La Jolla, CA, USA

    Maryla Krajewski, Stan Krajewski & John C Reed

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Correspondence to Garret M Hampton.

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Meinhold-Heerlein, I., Bauerschlag, D., Hilpert, F. et al. Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24, 1053–1065 (2005). https://doi.org/10.1038/sj.onc.1208298

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