As many as one in 10 adults worldwide develops a thyroid nodule that requires clinical investigation. The incidence of thyroid cancer is rapidly increasing, particularly among women, and although the majority of thyroid nodules are benign, each one must be thoroughly analyzed.
Up to one-third of patients, however, cannot be reliably diagnosed on the basis of a fine-needle aspiration biopsy of the thyroid and they all too frequently need to undergo invasive surgery to remove the affected lobe for further analysis. The majority of these cases are still benign, and surgery could be avoided if better diagnostic tools were available.
The research group at Trinity College is trying to identify robust early-stage markers that clearly indicate a thyroid nodule’s cancerous status from just a needle biopsy.
Thyroid cancers are divided into many different types, based on their pathologies. Papillary thyroid cancer (PTC) is the most commonly occurring type and accounts for about 80% of all thyroid tumors.
The team is looking for discrete molecular events in PTC tumor samples, such as the presence or absence of certain genes or gene products that always correlate with either a good or bad prognosis. Being able to diagnose a biopsy on the basis of such markers would be much more objective than classical cytological approaches and would hugely benefit cancer patients, as well as the healthcare system.
PTC studies have extensively researched three principal genes: the ret (rearranged during transfection) proto-oncogene, ras, and BRAF. ret-ras-BRAF form part of a common cellular signaling pathway.
Mutations in ret have been associated with the more malignant PTC tumors for some time (Figure 1). After the Chernobyl accident, for example, the incidence of thyroid cancers in Belarus showed a 2,500% increase. Part of the ret gene is known to be able to translocate within its chromosome and become juxtaposed to any one of 15 other genes. Each of these is always expressed in the cell, meaning that part of the ret gene becomes inappropriately activated. Two principal genes account for probably 90% of the changes: ret-1 and ret-3.
In the Dublin project, ret has been the major genetic aberration in PTC within the Irish population. ret-1 tends to associate with classic PTC, and ret-3 activation is associated with the more malignant tumors within the tissue sample cohorts being studied.
BRAF mutations on the other hand have shown an unusual temporal association. Up until 1992, the majority of tumors involved ret aberrations, but there has been a fairly dramatic change, and since then, tumors with BRAF mutations have become the most common in the Irish population samples.