Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

Abstract

ObjectiveTranscriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.MethodsGlobal gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.Results5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.ConclusionsThese data 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, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

“…Evolving technologies, in particular CRISPR-Cas9 genome editing, now enable precision modification of risk SNPs to create isogenic models of different alleles 35 , enabling the effects of each allele on disease pathogenesis to be studied, for example at 19p13 36 , 8q24 14 , 17q12 12 and 5p15 13 . Finally, given that several previously identified EOC susceptibility alleles are associated with risk of other cancers 17 , and that there are similarities in molecular phenotype and/or shared tissue of origin between endometrial cancer, endometriosis and ENOC and CCOC 37 as well as basal-like breast cancer 38 , we anticipate that the loci reported here may be also associated with risk of other cancer-related traits.…”

Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance

“…Targeting K5 + cells may also be effective in reducing recurrence in patients with serous ovarian carcinoma. Indeed many similarities have been observed between basal-like breast cancers and serous ovarian carcinoma [ 60 ].…”

Evaluating Serum Markers for Hormone Receptor-Negative Breast Cancer

“…We previously discovered Human epididymis protein 4 (HE4, WFDC2) as a marker for ovarian cancer, first as a transcript in tissue and, four years later, as protein in serum [ 23 , 24 ], and identified several other genes and serum markers that similarly discriminated ovarian cancer from controls [ 25 ]. Given the genomic similarities between the aggressive basal breast cancer subtype and serous ovarian cancer [ 26 , 27 ] and the hypothesis that biomarkers may overlap between these two subtypes [ 27 ], we investigated whether any of the serum markers that signal the presence of ovarian cancer could also signal presence of HRN or TN breast cancer.…”