Papillary thyroid cancer (PTC) is one of the few cancers whose incidence is on the rise. It is considered the most rapidly increasing of all cancers in Canada . Incidence has increased by 6.8% per year in males and 8.8% per year in females since 1998 in Canada with similar results noted in Europe and the United States . Risk factors for thyroid cancers include prior radiation, family history and genetics. Treatment by surgery and radio-iodine therapy is highly effective; however, due to the difficulty in accurate diagnosis of thyroid cancer, surgery is often performed on benign nodules. Benign thyroid masses such goiter, follicular adenomas and cysts are approximately ten times more common than thyroid cancers . Pre-operative diagnostic tests such as U/S, CT scan, and fine needle aspirate (FNA) often do not provide a definitive diagnosis. In these indeterminate cases, diagnostic hemithyroidectomy surgery is often performed and up to 75% of these patients have benign disease .
Research into the use of genomic techniques for improved diagnosis has focused on transcript profiling of well-differentiated thyroid cancer . Genes that appear to be up-regulated in these studies are numerous. Jazab et al. demonstrated in a group of 16 patients with PTC increased gene expression for lectin, galactoside-binding, soluble, 3 (LGALS3) which codes for galectin-3 (Gal-3) protein, tissue inhibitor of metalloproteinases 1 (TIMP1), and chitinase 3-like 1 (CHI3L1) which is also known as YKL-40 . Baris et al. noted high expression of adenosine deaminase (ADA), eukaryotic translation initiation factor 2 subunit 2 (EIF2S2), TIMP1, cyclin D1 (CCND1), cadherin-3 (CDH3) and collagen, type VIII, alpha 1 (COL8A1) in PTC . Niedźwiecki et al. explored the role of angiopoietin 1 and 2 in thyroid cancers, showing a negative correlation of angiopoietin-1 (Ang-1) with state of malignancy . Based on a review of these and other published studies using gene expression analysis, we concluded that YKL-40, Gal-3, cytokeratin 19 (CK19), TIMP-1 and Ang-1 were consistently found to be upregulated.
An alternative approach to tumor transcript profiling is protein profiling of serum. The main advantages of this approach are that it is minimally invasive, relatively safe and can be performed repeatedly. This could provide the basis for a useful test for screening, diagnosis, treatment and followup. However, the high complexity of serum makes identification of biomarkers challenging. Relative to healthy controls, the levels of serum vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) are elevated in late-stage PTC; however, as the levels of these markers do not differentiate between goiter and early stage PTC, they are not useful for improving diagnosis . Levels of biotinidase, clusterin, cysteine-rich, angiogenic inducer, 61 (CYR61), enolase 1, nucleolin and prothymosin alpha (PTMA) have been compared between PTC patients and healthy controls but no comparison was made with patients with benign nodules . In spite of these advances, there are currently no validated serum markers for the diagnosis of PTC or for risk stratification of thyroid masses.
Our objective was to identify potential serum markers in subjects with PTC. We hypothesized that markers that have been shown to be highly expressed in PTC tumor tissue, especially those that are secreted or present at the cell surface, would also be elevated in serum, and thus measurable by serum enzyme-linked immunosorbent assay (ELISA) analysis.