UCL Institute for Women's Health (IfWH)

Molecular Pathology Group

Leads: Dr Susan Ramus and Dr Christopher Jones

Background

Somatic genetic changes in cancer cells are important to the development of a tumour, especially in regard to its metastatic progression. The Molecular Pathology Group is developing and using DNA and tissue microarray technologies to profile the somatic changes present in ovarian tumours. These will help to identify novel genes associated with cancer initiation and progression, and also have potential uses in diagnostic applications.

Projects

CGH-Microarray Analysis of Malignant Ovarian Tumours

Lead: Dr Christopher Jones
The MALOVA study is a population-based epidemiological study of ovarian cancer cases from Denmark. As part of this study, FFPE sections of approximately 700 malignant tumours were collected, in addition to detailed clinical and lifestyle information from the patients. The Molecular Pathology Group is using the Mermaid CGH-microarray platform to generate high-resolution aCGH profiles from MALOVA tumour specimens, to correlate the somatic genetic profile of a tumour with histopathological and clinical data. In addition to helping to improve the classification of ovarian tumours, this detailed analysis will also help to identify novel genes associated with cancer initiation and progression, as well as patient survival.

Accurate Diagnosis of Synchronous Tumours

Leads: Dr Susan Ramus and Dr Christopher Jones
The ability to accurately diagnose dual primary tumours from metastases is important for the clinical management of cancer. We have previously shown that genetic analysis can be used to assess relationships between synchronous tumours of the ovary and endometrium [3] in order to determine whether they have arisen independently or if one is a metastases of the other. A PCR-based loss-of-heterozygosity (LOH) analysis was used, in conjunction with a statistical model and knowledge of the instability of specific genetic markers in the two tumour types [3]. CGH-microarray analysis provides a higher resolution analysis than this PCR-based approach, and it is hoped will provide better delineation of synchronous tumours. We are assessing the performance of our 32K CGH-microarray in the diagnosis of synchronous tumours, with the aim of developing a high-throughput diagnostic tool. Our original approach utilised knowledge of the instability of specific genetic markers in ovarian and endometrial tumours. Similarly, it is anticipated that detailed knowledge of the CGH profiles of ovarian and endometrial tumours will increase the statistical power of the CGH-microarray approach. In addition, this will also enable better experimental design of a diagnostic CGH-microarray, containing only replicated features from informative regions of the genome.

Tissue Microarray Analysis of Ovarian Tumours

Lead: Dr Susan Ramus
Tissue microarrays (TMAs) can be used to rapidly analyse the expression status of candidate protein markers in large populations of tumours. We have established the Ovarian Tumour Tissue Array (OTTA) consortium lead by Susan Ramus which brings together studies with invasive epithelial ovarian cancer TMAs. Currently tumours from over 4,000 individuals are available and an additional 4,000 cases will be arrayed by mid 2010. Within this consortium are TMAs from cases from the Ovarian Cancer Association Consortium (OCAC) and from case only series, including clinical trials.

We are currently analysing a subset of the OCAC TMAs with a panel of 10 markers that can be used to classify the histopathological subtype. This will be used to determine the quality of the pathology data in the OCAC database to assess if centralised pathology review is required. The correct classification of histological subtype is of particular importance, as many of the genetic associations identified by OCAC appear to be specific to a particular subtype.

A subset of these arrays have been used to assess the role of a candidate tumour suppressor gene in ovarian cancer by immunohistochemistry (IHC). The TMAs will be used in determining if candidate genes, identified by genome wide association studies (GWAS) and other studies, play a role in ovarian cancer and the large numbers should allow for stratification by histological subtype. Stage I and II GWAS data are available for 36% and 53% of the OCAC samples respectively and therefore the protein expression can be correlated with genotype. 

Members of the Molecular Pathology Group

• Dr Susan Ramus (Lecturer)
• Dr Christopher Jones (Senior Scientist)
• Eva Wozniak (Research Assistant)
• Tanya Lebi (Research Assistant)

Previous Members

• Ken Choi (PhD Student)
• Lalarukh Khalique (PhD Student)

Publications

1. Khalique L, Ayhan A, Whittaker J, Singh N, Jacobs I, Gayther SA, Ramus SJ. The clonal evolution of metastases from primary serous epithelial ovarian cancers. IJC 124:1579-86 (2009)
2. Dafou D, Ramus SJ, Choi K, Grun B, Trott DA, Newbold RF, Jacobs IJ, Jones C, Gayther SA. Neoplastic Suppression in Epithelial Ovarian Cancer Cells Lines by Microcell-mediated transfer of chromosomes 5, 6 and 18. IJC 124:1037-44 (2009)
3. Ramus SJ*, Elmasry K*, Luo Z, Gammerman A, Lu K, Ayhan A, Singh N, McCluggage WG, Jacobs IJ, Whitaker JC, Gayther SA. Predicting Clinical Outcome in Patients Diagnosed with Synchronous Ovarian and Endometrial Cancer Clin. Cancer Research 14:5840-8 (2008)
4. Khalique L, Ayhan A, Weale M, Jacobs IJ, Ramus SJ, Gayther SA. Genetic Intra Tumour Heterogeneity In Epithelial Ovarian Cancer: The Implications For Clinical Diagnostics. J Pathol. 211:286-95 (2007)
5. Ramus SJ, Pharoah PDP, Harrington P, Pye C, Werness B, Bobrow L, Ayhan A, Wells D, Fishman A, Gore M, Dicioccio R, Piver MS, Whittemore AS, Ponder BAJ, Gayther SA. BRCA1/2 Mutation Status Influences Somatic Genetic Progression In Inherited And Sporadic Epithelial Ovarian Cancer Cases. Cancer Research 63:417-423 (2003)