OvCaRe Discoveries
Ovarian Cancer Subtypes Can Be Diagnosed Consistently (PMID: 20505499)
Ovarian cancers can be divided into subtypes based on the cells found within the tumour. The various subtypes can essentially be considered as distinct diseases as they differ with respect to risk factors, prognosis, and response to therapy. Also, the choice of which ovarian cancer patients should be selected for genetic testing is partly based on the subtype of the disease. Thus, it is important for the diagnosis of these subtypes to be both reproducible and consistent between different centres and this will only become more critical as new subtype-specific therapies are developed. Recently, Köbel et al. demonstrated for the first time that with just routine histopathologic examination, a very high degree of reproducibility is achieved.
New Insight on Granulosa Cell Tumours of the Ovary
Granulosa cell tumours of the ovary are a particular subtype of ovarian cancer. They occur in approximately 1 out of every 100,000 women and account for less than 5% of all ovarian cancers. For women with granulosa cell tumours, the success of traditional chemotherapy has been limited and there is currently no therapy that is specific for this subtype of ovarian cancer.
Cancer results from changes or mutations in DNA. These changes are commonly detected by researchers through DNA sequencing. With traditional methods of DNA sequencing, specific areas of DNA have to be hand selected for analysis: a researcher has to suspect that a particular gene is mutated and then analyse the sequence of this gene to confirm the hypothesis. It is inconceivable to sequence all genes in order to look for a mutation in an unknown gene.
Recently, new technology has revolutionized research by making sequencing of the entire genome possible. Using this new sequencing technology, Shah et al. discovered that 97% of all granulosa cell tumours have an identical mutation in a gene called FOXL2 which results in the production of a mutant form of the FOXL2 protein. This is the first time that the use of this new sequencing technology has resulted in a discovery with immediate clinical relevance. The FOXL2 protein has been shown by other research groups to be critical in the normal development of granulosa cells and it is also a transcription factor. Transcription factors are responsible for the regulation of other genes by turning them ‘on’ or ‘off’. We believe that the mutation that is present in FOXL2 in granulosa cell tumours of the ovary disrupts this regulation, which ultimately results in uncontrolled growth of granulosa cells and cancer. This is the first finding that has provided some insight into what might trigger the formation of these tumours and provides a starting point for the development of therapies to target this subtype of ovarian cancer.
The treatment for granulosa cell tumours is often unsuccessful, and we hope that this discovery will lead to creation of more specific therapies for this disease. We believe that testing for the presence of the FOXL2 mutation may also improve diagnosis of granulosa cell tumours in problematic cases and could lead to earlier diagnosis of disease. This exciting discovery was featured in The Vancouver Sun, The Daily Telegraph and on Forbes.com.
Subtypes Count for Ovarian Cancer
Scientists are starting to recognize that divisions exist within particular cancers and better understanding of these cancer subtypes is the key to developing individualized therapies and diagnosis. This subtype specific approach is already being used for the treatment of breast cancer and lymphomas. Kobel et al. have recently shown that epithelial ovarian cancer subtypes are truly distinct diseases that must be studied as separate entities. These subtypes are classified based on their microscopic appearance as high-grade serous, low-grade serous, clear cell, endometrioid, or mucinous ovarian carcinoma. They differ with respect to genetic risk factors, underlying molecular events, average stage at diagnosis, responsiveness to treatment, and prognosis. Yet ovarian cancer is typically treated as a single disease. The research of Kobel et al. examined the presence of molecules found in cancer cells that are used to diagnose disease (‘biomarkers’) within epithelial ovarian cancer subtypes and found that the presence of a particular biomarker is more strongly associated with a specific subtype as opposed to stage of disease. Further, the presence of a particular biomarker within a subtype is consistent across stages, which has important implications for earlier diagnosis of disease. Finally, the presence of particular biomarkers can help to predict outcome, but this prediction is subtype-specific. This research shows that it is misleading to group all subtypes of ovarian cancer together in studies. This is particularly relevant for the clear cell and mucinous subtypes which are in great need of more effective and targeted therapies. This exciting discovery was featured in the Vancouver Sun in December 2008.
Extending the Potential of Ovarian Cancer Animal Models
An animal model of disease is a critical resource for the study of cancer. These models make it possible to test new therapies and to study the progression of disease in a complete living system. Dr. YZ Wang’s research group is part of the OvCaRe team and has been at the forefront of developing xenograft mouse models of ovarian cancer: these models are created by taking human tumour tissue and transplanting it into a mouse. This transforms the mouse into an ovarian cancer model for the study of the transplanted tumour. This resource was limited, however, by the life span of the mouse. Now Press et al. have successfully extended the life of xenograft mouse models by transferring tumour tissue from one mouse to another mouse, thereby making it possible to use the model over several generations. The transferred tumours also sustain minimal genetic change over time and so accurate reflection of the source tumour is maintained with respect to expression of cancer molecules and reaction to treatment. This technique provides a renewable preclinical model to test developing therapeutics and will also allow analysis of tumour progression at the cellular and molecular levels over an extended period of time.
Distinguishing Different Mechanisms of BRCA1 Loss in Ovarian Cancer
Though BRCA1 is most commonly recognized as a breast cancer susceptibility gene, it is also associated with ovarian cancer. High grade serous tumours, which are the most common type of ovarian cancer, often lack of BRCA1. This can occur either through mutation of the BRCA1 gene itself or through DNA silencing mechanisms that occur in regions of DNA close to the BRCA1 gene. As therapies become more targeted towards specific defects, it is important to be able to distinguish high grade serous cancers that have BRCA1 mutations from those with silenced BRCA1. It is perhaps even more important to distinguish these two groups from those high grade serous cancers with normal BRCA1. Further, it is critical to make these distinctions in a timely manner so that patients are not made to wait unnecessarily for individualized therapies. Press et al. have recently shown that these three categories of high grade serous cancers can be sorted based on their expression on a panel of markers. Interestingly, high grade serous cancers with BRCA1 mutations and those with silenced BRCA1 both had disrupted regulation of the same common signalling pathway within the cell, but through different mechanisms. In both of these groups, activation of the P13K/AKT pathway was observed which is significant as activation of this pathway has been shown to decrease the effectiveness of traditional taxane therapy. However, new therapies are being developed that will more specifically target this pathway and when this happens, it will be critical to be able to quickly identify those cancers that are most likely to benefit from this approach.
