19p13.11

Thyroid cancer

NIS-mediated uptake of radionuclides has long been exploited in diagnostic scintigraphic imaging (¹²³I, ¹³¹I, ^99mTcO4^-) and radiotherapy (¹³¹I) of thyroid carcinoma of follicular cell origin. Compared to other cancers, the prevalence of thyroid cancer is relatively low and its prognosis after surgery and radioiodine therapy is mostly favorable. However, radioiodine uptake is frequently decreased in differentiated thyroid carcinoma (papillary and follicular) and is completely absent in 20% of differentiated carcinomas and most anaplastic thyroid carcinomas. Furthermore, the recurrence rate of thyroid cancer is high (10-30% for papillary thyroid carcinoma) and only one third of patients with distant metastases respond to ¹³¹I therapy with complete remission.
NIS expression in thyroid cancer is controversial with reports of under-expression as well as over-expression (Arturi et al., 1998; Saito et al., 1998; Venkataraman et al., 1999; Lazar et al., 1999; Castro et al., 2001; Dohan et al., 2001; Ward et al., 2003; Trouttet-Masson et al., 2004). Low NIS expression identifies aggressive thyroid tumors and correlates with reduced radioiodine uptake and tumor dedifferentiation. Loss of NIS expression may be associated with hypermethylation of the NIS gene promoter, or may be secondary to reduced expression of nuclear transcription factors. When over-expressed, NIS is mostly intracellular suggesting defective targeting of the protein to the plasma membrane in these cases. Hypofunctioning thyroid tumors express low levels of non-glycosylated NIS suggesting that protein maturation may also be impaired.
Several pharmacological approaches are being tested for their ability to promote cellular re-differentiation, increase endogenous NIS expression and restore iodide transport in thyroid carcinoma cell lines and in patients. Agents include retinoic acid, demethylating agents, histone deacetylase inhibitors and reverse transcriptase inhibitors (Schmutzler et al., 1997; Venkataraman et al., 1999; Zarnegar et al., 2002; Fortunati et al., 2004; Landriscina et al., 2005). The effectiveness of these agents, however, is variable and their clinical utility has yet to be proven.

Although no somatic NIS mutations have been identified in thyroid carcinoma, alterations in other genes or gene products may be associated with NIS impairment.
BRAF: Papillary thyroid carcinomas (PTC) harboring the BRAF V600E mutation have reduced NIS expression and impaired targeting to the plasma membrane, which correlates with reduced radioiodine uptake and high risk of recurrence (Riesco-Eizagirre et al., 2006). BRAF V600E-positive PTC also have reduced expression of other thyroid-specific genes such as thyroperoxidase and thyroglobulin, suggesting that impaired NIS expression may be part of an early dedifferentiation process present at the molecular level in BRAF V600E-mutated PTC (Durante et al., 2007; Romei et al., 2008).
RET/PTC: Expression of RET/PTC rearrangements reduces radioiodide uptake and NIS expression in thyroid cells in vitro and transgenic mice (Cho et al., 1999; Knauf et al., 2003). No change in NIS expression, however, was detected in papillary thyroid carcinoma with RET/PTC rearrangements (Romei et al., 2008).
PTTG: Differentiated thyroid cancer over-expresses pituitary tumor transforming gene (PTTG), a proto-oncogene involved in the control of sister chromatid separation. PTTG overexpression correlates with reduced radioiodine uptake and is a prognostic factor for persistent disease (Saez et al., 2006). PTTG downregulates NIS expression and I^- uptake in vitro, possibly by repressing the binding of transcriptional regulators to the hNUE upstream enhancer (Boelaert et al., 2007).

Breast cancer

NIS is up-regulated in breast cancer and attention has recently focused on the potential application of radioiodine in the diagnosis and therapy of breast cancer. Several studies have detected NIS immunohistochemically in 30-90% of primary and metastatic breast carcinomas, with variable degrees of intracellular and plasma membrane staining (Tazebay et al, 2000; Wapnir et al, 2003; Wapnir et al., 2004; Beyer et al., 2008; Renier et al., 2009). Estimates of NIS expression in breast cancer, however, may be overestimated due to non-specific binding of some anti-NIS antibodies resulting in a diffuse intracellular staining. One study failed to detect significant NIS immunostaining in 30 cases of primary breast cancer (Peyrottes et al., 2009). In vivo scintigraphic imaging detected ¹²³I or ^99mTcO4 uptake in up to 25% of NIS-expressing breast tumors, suggesting that the expression of functional NIS in breast cancer is low (Moon et al., 2001; Wapnir et al., 2004). Current research is aimed at identifying strategies that increase the expression and membrane targeting of NIS in breast cancer, in order to improve the efficiency of NIS-mediated radionuclide uptake.

Cholangiocarcinoma (CCA)

NIS is up-regulated in CCA and is localized to the plasma membrane and/or cytoplasm of bile duct epithelial cholangiocytes. In the diethylnitrosamine rat model of liver cancer, NIS is expressed at the preneoplastic stages of liver carcinogenesis and enables tumor suppression after ¹³¹I radiotherapy (Liu et al., 2007). Radioiodide therapy may therefore represent a novel strategy for the treatment of CCA.

Gastric cancer

NIS expression, normally present in the gastric mucosa, is markedly decreased or absent in gastric cancer (Altorjay et al., 2007) and distinguishes malignant from benign gastric lesions (Farnedi et al., 2009).

Various carcinomas

Targeted NIS gene therapy is being evaluated as a potential diagnostic and therapeutic option for various cancers, enabling tumor cells to accumulate NIS-transported radionuclides. Preclinical studies demonstrate NIS expression, radioiodide uptake and tumor cell death in vitro and in vivo following targeted adenoviral NIS gene transfer to tumor cells. A phase I clinical trial is ongoing to study the efficacy and safety of NIS gene therapy and radioactive iodine for the treatment of prostate cancer (NCT00788307, www.clinicaltrials.gov).

Carcinomas of the prostate, cervix, breast, head and neck, lung, liver, thyroid, colon, ovaries and pancreas; myeloma; glioma.

Thyroid adenoma

Benign nonfunctioning thyroid adenomas are characterized by reduced radioiodine uptake due to reduced NIS expression or defective targeting of NIS to the plasma membrane (Tonacchera et al., 2002). A loss-of-function deletion of exon 6 of the NIS gene was identified in a single case of follicular thyroid adenoma (Liang et al., 2005). Hyperfunctioning toxic adenomas harbor activating mutations of the TSH receptor and are characterized by increased NIS expression with correct plasma membrane localization (Lazar et al., 1999).

Congenital Hypothyroidism

Germinal NIS mutations causing iodide transport defect (ITD) are a rare cause of dyshormogenic congenital hypothyroidism (OMIM 274400). To date, 12 mutations have been reported (V59E, G93R, R124H, ΔM143-Q323, Q267E, C272X, T354P, G395R, ΔA439-P443, frame-shift 515X, Y531X, G543E) leading to reduced or absent thyroidal radioiodine uptake, low iodide saliva: plasma ratios and a variable degree of hypothyroidism and goiter.

Goitre, severe neuro-developmental impairment and infertility if not treated. Hypothyroidism treated with T4-replacement therapy and I^- supplementation.