Intrinsic subtypes and prognostic implications in epithelial ovarian cancer

Sammanfattning: Ovarian cancer is the seventh most common cancer in women globally, with approximately 240,000 new cases annually. Although a rare disease, it is the most lethal gynecologic malignancy. Unspecific symptoms result in late diagnosis and a generally poor prognosis. However, ovarian cancer is a heterogeneous disease comprising different disease entities, which is of importance in clinical decision-making as well as in research. This thesis describes explorative approaches to investigate the ovarian cancer heterogeneity in a hereditary ovarian cancer subset and in histopathological and molecular subtypes of ovarian cancer. In study I, a gene expression profile differentiating the rare subgroup of Lynch syndrome-associated ovarian cancer from a matched sporadic cohort was identified. The Lynch syndrome-related expression profile was associated with proliferation and cell death processes. An external dataset was used to refine the gene expression profile, but validation with immunohistochemical staining of key proteins did not reveal any differences between the hereditary and sporadic cases. A distinct cluster of hereditary serous and endometrioid cancers was seen, whereas clear cell carcinomas (OCCCs) clustered together, whether hereditary or sporadic. In study II, gene expression profiling of OCCCs revealed extensive inter-tumor heterogeneity. Targeted deep sequencing of 60 cancer-related genes in an OCCC cohort revealed frequent mutations of chromatin remodeling genes, including mutations not previously reported in ovarian cancer. These results remain to be validated. Study III outlined gene expression profiles in malignant, borderline, and benign serous ovarian tumors. Pre-defined molecular subtypes of ovarian cancer as well as intrinsic breast cancer subtypes were applied to our cohort. Associations between the most aggressive ovarian cancer subtypes and the basal-like breast cancer subtype were identified. The results were validated using a large, external dataset. Furthermore, associations between borderline ovarian tumors and the luminal A breast cancer subtype were discovered. The luminal A breast cancer subtype characterizes hormone receptor positive breast cancer. In study IV, we therefore outlined the protein expression of estrogen receptor (ER) α, ERβ, the progesterone receptor (PR), and the androgen receptor (AR) as well as the prognostic effect of receptor expression in serous and endometrioid ovarian cancer. Expression of PR and AR was associated with a favorable prognosis, and co-expression of PR and AR conferred an additional prognostic benefit. The mRNA levels of the encoding genes were investigated in the molecular subtypes of ovarian cancer using an external dataset. The expression varied between the different subtypes, but no prognostic benefit of dual high PGR and AR levels were revealed. In conclusion these studies further characterize the ovarian cancer heterogeneity, and support that future ovarian cancer studies need to be stratified for both histopathologic subtypes and molecular features