RET/PTC Rearrangements Are Associated with Elevated Postoperative TSH Levels and Multifocal Lesions in Papillary Thyroid Cancer without Concomitant Thyroid Benign Disease

<div><p>RET/PTC rearrangements, resulting in aberrant activity of the RET protein tyrosine kinase receptor, occur exclusively in papillary thyroid cancer (PTC). In this study, we examined the association between RET/PTC rearrangements and thyroid hormone homeostasis, and explored whether concomitant diseases such as nodular goiter and Hashimoto's thyroiditis influenced this association. A total of 114 patients diagnosed with PTC were enrolled in this study. Thyroid hormone levels, clinicopathological parameters and lifestyle were obtained through medical records and surgical pathology reports. RET/PTC rearrangements were detected using TaqMan RT-PCR and validated by direct sequencing. No RET/PTC rearrangements were detected in benign thyroid tissues. RET/PTC rearrangements were detected in 23.68% (27/114) of PTC tissues. No association between thyroid function, clinicopathological parameters and lifestyle was observed either in total thyroid cancer patients or the subgroup of patients with concomitant disease. In the subgroup of PTC patients without concomitant disease, RET/PTC rearrangement was associated with multifocal cancer (P = 0.018). RET/PTC rearrangement was also correlated with higher TSH levels at one month post-surgery (P = 0.037). Based on likelihood-ratio regression analysis, the RET/PTC-positive PTC cases showed an increased risk of multifocal cancers in the thyroid gland (OR = 5.57, 95% CI, 1.39–22.33). Our findings suggest that concomitant diseases such as nodular goiter and Hashimoto's thyroiditis in PTC may be a confounding factor when examining the effects of RET/PTC rearrangements. Excluding the potential effect of this confounding factor showed that RET/PTC may confer an increased risk for the development of multifocal cancers in the thyroid gland. Aberrantly increased post-operative levels of TSH were also associated with RET/PTC rearrangement. Together, our data provides useful information for the treatment of papillary thyroid cancer.</p></div

Association between RET/PTC rearrangement and pathological parameters in thyroid cancer patients.

<p>Association between RET/PTC rearrangement and pathological parameters in thyroid cancer patients.</p

Association between RET/PTC rearrangements and changes in thyroid function in thyroid cancer patients.

<p>Association between RET/PTC rearrangements and changes in thyroid function in thyroid cancer patients.</p

Association between haplotypes of RET tagSNPs and susceptibility to thyroid cancer.

<p>Association between haplotypes of RET tagSNPs and susceptibility to thyroid cancer.</p

Association between RET/PTC rearrangement and thyroid function in thyroid cancer patients without nodular goiter or Hashimoto's thyroiditis.

<p>Association between RET/PTC rearrangement and thyroid function in thyroid cancer patients without nodular goiter or Hashimoto's thyroiditis.</p

Association between haplotypes of RET tagSNPs and the occurrence of distant metastasis in thyroid cancer.

<p>Association between haplotypes of RET tagSNPs and the occurrence of distant metastasis in thyroid cancer.</p

Association between RET tagSNP and clinicopathological features of thyroid cancer.

<p>Association between RET tagSNP and clinicopathological features of thyroid cancer.</p

Associations between <i>RET</i> tagSNPs and their haplotypes and susceptibility, clinical severity, and thyroid function in patients with differentiated thyroid cancer

<div><p>Background</p><p>It is unclear whether common genetic variants of the <i>RET</i> proto-oncogene contribute to disease susceptibility, clinical severity, and thyroid function in differentiated thyroid cancer (DTC).</p><p>Methods</p><p>A total of 300 DTC patients and 252 healthy controls were enrolled in this study. Seven RET tagging single nucleotide polymorphisms were genotyped using the KASPar platform.</p><p>Results</p><p>Subgroup analysis showed that concomitant thyroid benign diseases were less likely to occur in DTC subjects with the rs1799939 AG or AG plus AA genotypes (odds ratio (OR) = 1.93 and 1.88, P = 0.009 and 0.011, respectively). A rare haplotype, CGGATAA, was associated statistically with a reduced risk of DTC (OR = 0.18, P = 0.001). Concerning the aggressive features of DTC, higher level of N stage was more likely to occur in subjects carrying the wild-type genotypes at rs1800860 site (for dominant model: OR = 0.48, P = 0.008). Another rare haplotype, CAAGCGT, conferred increased risk for the occurrence of distant metastasis (OR = 7.57, P = 0.009). Notably, higher thyroid stimulating hormone levels and lower parathyroid hormone levels were found in patients with rs2075912, rs2565200, and rs2742240 heterozygotes and rare homozygotes; similar results were observed between PTH levels and rs1800858.</p><p>Conclusion</p><p>This study provided useful information on <i>RET</i> variants that should be subjected to further study.</p></div

Association between RET/PTC rearrangement and lifestyle of patients with thyroid cancer.

<p>Association between RET/PTC rearrangement and lifestyle of patients with thyroid cancer.</p

Amplification and sequencing of RET/PTC variants.

<p>The qRT-PCR amplification curves show amplification of RET/PTC1, 2 and 3 (red curves) and GAPDH control (green curve). (A) Tumor with the RET/PTC1 fusion gene. (B) Tumor without the RET/PTC2 fusion gene. (C) Tumor without the RET/PTC3 fusion gene (D) DNA sequencing analysis of PCR products containing RET/PTC1. (E) DNA sequencing analysis of PCR products containing RET/PTC2. (F) DNA sequencing analysis of PCR products containing RET/PTC3.</p