Functional Genomics Laboratory

Head of laboratory

Associate Professor Deborah Marsh

Research Assistant Kristie-Ann Dickson is using cell lines for functional studies of ovarian and parathyroid cancer.

Overview of research program

Our laboratory studies the molecular biology of sporadic and inherited tumours, as well as generalised cellular overgrowth. We have a long term interest in PTEN and the phosphatidylinositol 3-kinase (PI3-K) pathway with ongoing studies in this area in the context of endometrial and ovarian cancer, as well as the overgrowth disorder Proteus syndrome. An aspect of our work in this area was featured on the ABC program Catalyst in 2008. Two major research areas are highlighted below.

Parafibromin – roles of a novel tumour suppressor

Dr Michael Hahn is investigating the functions and binding partners of parafibromin.

Our laboratory has made major contributions to the study of the tumour suppressor parafibromin (encoded by HRPT2), being the first to link somatic mutations in HRPT2 to sporadic parathyroid cancer and elucidate the cellular localisation of this protein. This protein is a member of the PAF1 complex so likely has a critical role in RNA polymerase II mediated transcription. HRPT2 is one of over thirty familial cancer genes so can be grouped with other genes that have a role in both familial and sporadic cancers such as PTEN, TP53, BRCA1 and MEN1. Our work in this area has been translated to the clinical pathology laboratory and is now used routinely to facilitate the diagnosis of parathyroid cancer.

Ongoing studies are designed to elucidate binding partners of parafibromin and the many roles this protein plays in the maintenance of healthy cells and in malignancy.

Ovarian cancer

Targeting the surface epithelial cells of the mouse ovary. Blue staining indicates LacZ expression that has been activated by sub-bursal delivery of AdCRE in floxed LacZ mice. Blue staining is seen only in the ovarian surface epithelium. (Image taken by Dr V Howell)

Ovarian cancer has the worst prognosis of all of the gynaecological malignancies with an urgent need to identify new diagnostic markers and molecules in signalling pathways amenable to targeted therapeutics. We have an emerging research program in this area with projects including:

Immunofluorescent image of ovarian cancer cell line OV207 following FSH treatment. Staining for phosphorylated Pyk2[TYR402] (green) shows localization to focal adhesions. Nuclei stained with DAPI (blue). Image taken by PhD student Inga Mertens.

Investigation of the role of the gonadotropins luteinising hormone (LH) and follicle stimulating hormone (FSH) in the development of ovarian cancer using both cell line and mouse models
investigation of the role of chemokines in ovarian tumorigenesis
the role of miRNAs and their interactions with common signalling pathways in ovarian cancer
development and characterisation of mouse models of ovarian epithelial cancer using Sleeping Beauty insertional mutagenesis.

Tumour banking

Tumour Bank Officer, Ussha Pillai storing tumour specimens for research.

Additionally, our group includes the Kolling Institute's Tumour Bank staff responsible for collecting tumours and maintaining databases for the Breast, Gynaecological, Upper Gastrointestinal and Neuroendocrine Banks from Royal North Shore and nearby hospitals. We are also a collection site for the NSW Breast Cancer Tissue Bank. The blood and tumour specimens housed in these banks are invaluable in the facilitation of translational research programs.

Major funding sources

Cancer Institute NSW
Cure Cancer Australia
National Breast Cancer Foundation
National Health and Medical Research Council
NSW Cancer Council

Selected publications

Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O, Marsh DJ. Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2009; 94(2):434-41.

Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk E, Baxter RC, Marshall GM. Molecular targeted therapy for an overgrowth syndrome: Rapamycin tretment for a child with germline PTEN mutation. Nature Clinical Practice Oncology 2008; 5(6):357-361.

Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM, Marsh DJ. Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and Hyperparathyroidsim-Jaw Tumor (HPT-JT) syndrome related adenomas from sporadic parathyroid adenomas and hyperplasias. American Journal of Surgical Pathology 2006; 30(9):1140-1149.

Moscova M, Marsh DJ, Baxter RC. Protein-chip discovery of secreted proteins regulated by the phosphatidylinositol 3-kinase pathway in ovarian cancer cell lines. Cancer Research 2006; 66(3):1376-1383.

Hahn MA and Marsh DJ. Identification of a functional bipartite nuclear localisation signal in the tumour suppressor parafibromin. Oncogene 2005; 24(41): 6241-6248.

Haven CJ*, Howell VM*, Eilers PHC, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievet J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ and Teh BT. Gene expression of parathyroid tumours: molecular subclassification and identification of the potential malignant phenotype. Cancer Research 2004; 64: 7405-7411. (* These authors have contributed equally)

Marsh DJ, Morreau H and Teh BT, HRPT2 and parathyroid cancer. Lancet Oncology 2004, 5: 78.

Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumors. Journal of Medical Genetics 2003; 40: 657-663.

Smith JM, Kirk, EPE, Theodosopoulos G, Marshall G, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ. Germline mutation of the tumour suppressor PTEN in Proteus Syndrome. Journal of Medical Genetics 2002; 39: 937-940.

Marsh DJ, Zori RT. Genetic insights into familial cancers – Update and recent discoveries. Cancer Letters 2002; 181:125-164.
Liaw D*, Marsh DJ*, Li J, Dahia PLM, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics 1997; 16:64-67. (* These authors have contributed equally)

Marsh DJ, Dahia PLM, Zheng Z, Parsons R, Gorlin RJ, Eng C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nature Genetics 1997; 16:333-334.

Major collaborations

International

Professor Oliver Gimm, University Hospital Linköping, Linköping, Sweden
Dr Bin Teh, Van Andel Research Institute, Grand Rapids, MI, USA
Dr Neal Copeland and Dr Nancy Jenkins, Institute of Molecular and Cell Biology, Singapore
Dr Muhammad Zaman, Boston University, MA, USA.

NSW and local

Dr Anthony Gill, Anatomical Pathology, Royal North Shore Hospital
Dr Charles Allan, ANZAC Research Institute
A/Prof Christine Clarke, Westmead Millenium Institute (State Breast Tumour Banking)
Dr Robert Dunne, CSIRO Mathematical and Information Sciences
Professor Robert Baxter, Kolling Institute of Medical Research
Dr Janet Martin, Kolling Institute of Medical Research

Research project opportunities

Supervised by Associate Professor Deborah Marsh

Kolling Institute of Medical Research

Medical research matters