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High-resolution genome-wide copy number analysis of pre-invasive mucinous ovarian tumours

ABSTRACT: Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39076 | GEO | 2012/08/26

SECONDARY ACCESSION(S): PRJNA170106

REPOSITORIES: GEO

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Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as “C-signatures”) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as M-bM-^@M-^\C-signaturesM-bM-^@M-^]) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers. Total RNA obtained from serous ovarian adenocarcinomas, adenomas and borderline tumors. Gene expression profiling using Illumina's HT12 v4 bead arrays. Application of ovarian cancer molecular subtypes and intrinsic breast cancer subtypes using nearest centroid classification. KRAS and BRAF mutation analyses in the malignant and borderline tumors.

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High-resolution genome-wide copy number analysis of pre-invasive mucinous ovarian tumours

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