Cancer Genetics Thyroid Laboratory

Head of Laboratory

Dr Martyn Bullock is investigating the transcriptional functions of PAX8-PPARγ in follicular thyroid cancer.
Dr Martyn Bullock is investigating the transcriptional functions of PAX8-PPARγ in follicular thyroid cancer.

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Overview of research program

The Cancer Genetics Thyroid Laboratory is focused on understanding the genetic factors that contribute to the development of follicular and parafollicular derived thyroid cancers that respond poorly to current chemo- and radio-therapies.

Follicular thyroid cancer

We have focused on a fusion protein that is present in at least 50% of follicular thyroid cancers, namely PAX8-PPARγ. We have shown that PAX8-PPARγ has mixed transcriptional function, in that it stimulates some (but not all) PAX8 genes as well as some (but not all) PPARγ gene targets. For instance, we have shown that the PPARγ target genes aquaporin 7, angiopoeitin-like 4 and enolase 3 are all upregulated in thyroid cancers containing PAX8-PPARγ. The specific and substantial upregulation of aquaporin 7 (a glycerol channel) is particularly important as it identifies a potential source of cellular energy. The most important PAX8 gene target that we have studied is that encoding the sodium-iodine symporter gene. This is a key target in thyroid cancer management since its expression is the means by which metastases are ablated using radioactive iodine. Since PPARγ is a receptor for thiazolidinediones (a new class of therapy for diabetes) we hypothesize that this treatment will allow re-expression of the sodium-iodide symporter in thyroid cancers that have become resistant to iodine therapy.

Our basic transcriptional insights are therefore directly relevant for identifying new therapies for thyroid cancer.

Medullary thyroid cancer

PhD student Dr Deepak Abraham is using microarray technology to identify genetic changes in sporadic MTC.
PhD student Dr Deepak Abraham is using microarray technology to identify genetic changes in sporadic MTC.

Medullary thyroid carcinoma (MTC) is a malignancy arising from C-cells of the thyroid and is primarily treated by surgery. Many patients develop metastatic disease that remains difficult to treat due to the limited responsiveness of this tumour to chemotherapy, radiotherapy and imaging. The tumour occurs either in a sporadic form (75%) or a hereditary form (25%) Gain of function mutations in the RET proto-oncogene are found in hereditary forms and in 30-50% of sporadic MTCs. Screening for germline RET mutations is routine practice in patients with MTC and has enabled the identification of RET mutation carriers who are at risk of developing MTC. However the genetic basis for the development of sporadic MTC (sMTC) without somatic RET mutations remains unknown.

We are interested in understanding the genetic changes that occur in MTC, in particular sporadic MTC that do not carry a RET gene mutation which may elucidate non-RET oncogenic events in human MTC development, and aid discovery of potential new targets for therapy and improved disease management.

Gene profiling studies using microarray technology are currently being conducted on MTC tumours from the Neuroendocrine Tumour Bank to identify genetic expression markers associated with prognosis and elucidate the role of such regulatory molecules as micro RNAs in the predisposition and development of sporadic MTC.

Genetic predictive RET testing

Major funding sources

  • Cancer Council NSW
  • Royal Australasian College of Surgeons
  • Mary Debattista Cancer research Fund, RNSH
  • G Baker Trust Fund, RNSH, Kolling Institute

Selected publications

Lee JJ, Au AY, Foukakis T, Barbaro M, Kiss N, Clifton-Bligh R, Staaf J, Borg A, Delbridge L, Robinson BG, Wallin G, Hoog A, Larsson C. Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma. Endocr Relat Cancer. 2008;15:801-15.

Giordano TJ, Au A, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG, Vinco M, Misek DE, Sanders D, Zhu Z, Ciampi R, Hanash S, Chinnaiyan A, Clifton-Bligh RJ, Robinson BG, Nikiforov YE, Koenig RJ. Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation. Clin Cancer Res 2006;12:1983-1993.

Foukakis T, Au AY, Wallin G, Geli J, Forsberg L, Clifton-Bligh R, Robinson BG, Lui WO, Zedenius J, Larsson C. The Ras Effector NORE1A is Suppressed in Follicular Thyroid Carcinomas with a PAX8-PPARgamma Fusion. J Clin Endocrinol Metab. 2006;91:1143-1149.

Au AY, McBride C, Wilhelm KG Jr, Koenig RJ, Speller B, Cheung L, Messina M, Wentworth J, Tasevski V, Learoyd D, Robinson BG, Clifton-Bligh RJ. PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth. Endocrinology. 2006;147:367-76.

Cheung L, Messina M, Gill A, Clarkson A, Learoyd D, Delbridge L, Wentworth J, Philips J, Clifton-Bligh R, Robinson BG. Detection of the PAX8-PPAR fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2003;88:354-357.

Marsh DJ, Theodosopoulos G, Martin-Schulte K, Richardson AL, Philips J, Röher HD, Delbridge L, Robinson BG. Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003 Apr;88(4):1866-72

Major collaborations

Follicular thyroid cancer

  • Prof C Larsson (Karolinska Institute, Stockholm, Sweden)
  • Prof R Koenig (University of Michigan, USA)
  • Prof Leigh Delbridge (Department of Surgery RNSH)
  • Dr Mark Sywak (Department of Surgery RNSH)

Medullary thyroid cancer

  • Prof Leigh Delbridge (Department of Surgery RNSH)
  • Dr Mark Sywak (Department of Surgery RNSH)
  • Dr Herbert Chen, MD (University of Wisconsin, USA)

Research project opportunities

Supervised by Professor Bruce Gregory Robinson