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Trinity s Orla Sheils on Tackling Papillary Thyroid Cancer with Arrays

Orla Sheils
Senior Lecturer in Molecular Pathology
Department of Histopathology, Trinity College Dublin

Name: Orla Sheils

Title: Senior Lecturer in Molecular Pathology, Department of Histopathology, Trinity College Dublin

Education: 1999 — PhD, University of Dublin, Trinity College; 1991 — Fellowship of the Academy of Medical Laboratory Science; 1985 — BSc, biomedical science, Dublin Institute of Technology.

Orla Sheils is a senior lecturer in molecular pathology in the department of histopathology at the University of Dublin's Trinity College. She is also an investigator at Dublin's St. James Hospital.

Sheils recently crossed the Atlantic and then some to participate in Applied Biosystem's symposium, held last month concurrently with the American Society of Human Genetics conference in Salt Lake City.

Of interest to ABI symposium attendees? Sheils' work using the company's 1700 Chemiluminescent Microarray Analyser in her work on papillary thyroid cancer, as well as a forthcoming publication that will deal with the results of a study that discovered biomarkers for diagnosing the troublesome follicular variant of papillary thyroid carcinoma from the lesions it produces.

To learn more about Sheils work, BioArray News corresponded with her by e-mail this week.

Can you give me a little information about your professional background? How did you wind up at Trinity working on papillary thyroid cancer?

I studied biomedical science [at the Dublin Institute of Technology] and following my undergraduate studies began a job in a research position in the Histopathology Department at Trinity College Dublin.

While in that role I undertook a PhD in the area of thyroid cancer under the supervision of Eamon Sweeney. I was subsequently appointed lecturer and then senior lecturer in molecular pathology in the department.

Can you describe the current state of testing for PTC, particularly FV-PTC?

Current testing involves conventional histopathological and morphological assessment with immunohistochemistry as an adjunctive diagnostic tool. Often, fine needle aspiration samples are taken first and sent to the cytopathology lab and, if indicated, a follow-up surgical resection is performed. FV-PTC can be a problematic lesion to diagnose using these methods, as the morphological picture may not always be clear. I can't provide you with an exact statistic of successful diagnoses, but it is widely known to be problematic.

Why did you decide to use microarray technology to investigate ways to make a diagnosis of FV-PTC?

We were involved in examining molecular triggers in PTC development, particularly focusing on ret/PTC variants and BRAF mutations, with a view to understanding the molecular pathways involved as a consequence of these aberrations.

This conventional approach to functional genomics has drawbacks in that it typically involves analysis of a gene at a time. Whole-genome interrogation provided us with an opportunity to generate an aerial view of the genetic signatures of these lesions, corroborating the targets we were interested in as key features of disease progression and identifying novel targets and pathways.

It has helped us tie together some patterns of gene expression and thus to understand a bit more clearly the molecular pathobiology.

Can you describe what kind of professional relationship Trinity has had with Applied Biosystems in the past?

To the best of my knowledge, Trinity has no structured professional relationship with AB. However, John O'Leary — who now heads the department of histopathology — and I both collectively and individually have used molecular tools provided by AB and have collaborated on several research projects. We have acted as a customer test site for novel kits and chemistries and have a number of ongoing collaborations in a wide range of research applications.

Why did you decide to use the 1700 system and TaqMan PCR assays for this investigation?

The 1700's chemiluminescent system with its inherent enhanced sensitivity, coupled with the probe design and structure, drew us to the 1700 platform. We were impressed by the quality control measures intrinsic to the system. The prospect of a whole-genome array was [also] compelling and encouraged us to use the system.

TaqMan is the gold standard in quantitative RT-PCR and was used to validate the data obtained from the 1700 system. The validation was undertaken in keeping with best practice [and also] because the system is new to the arena.

Can you describe your methodology and what you found?

We identified clear sets of genes, which were associated with benign or malignant phenotypes. In addition we could sub-classify classical PTC and FV-PTC. The current study is being expanded to include other sub-variants of PTC and other forms of thyroid cancer.

What genes were specifically up-regulated and down-regulated?

We generated lists of genes differentially expressed in malignant vs. benign thyroid tissue.

Two-tail analysis of variants with p-value correction yielded 173 probes — 52 up-, 121 down-regulated in PTC — significantly different between the malignant and benign thyroid tissues.

However, importing those lists into [Applied Biosystem's] Panther software grouped many of the individual targets into relevant biological pathways or mechanisms, thereby highlighting important biological processes segregating with benign and malignant lesions.

What potential exists to use the new information in future diagnostic tests?

There is potential from a number of angles. A greater level of understanding of the underlying molecular processes in PTC development is possible using the data generated, [so] by increasing our understanding, we may target our attention to markers associated with particular sub-types of PTC and in that way assist and augment current diagnostic practice.

We [also] plan to use a TaqMan low-density array with 40-50 targets identified from whole-genome analysis in a research study to investigate its ability to characterize specific PTC lesions.

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