Detection of the PAX8-PPAR Fusion Protein in Thyroid Tumors

Nobody wants to get cancer, but if you have to, thyroid cancer is a good one to get because of its excellent prognosis. Still, there is plenty of room for improvement in the current approaches to the diagnosis and therapy of this disease. Thyroid cancer is the most common endocrine malignancy. The American Cancer Society estimates 37 000 new cases of thyroid cancer were diagnosed in the US in 2008. The National Cancer Institute Surveillance Epidemiology and End Results database indicates that nearly 400 000 living Americans have a history of thyroid cancer and that 1 in every 127 Americans will be diagnosed with thyroid cancer during his or her lifetime. The vast majority of cases are so-called differentiated thyroid cancers, which are characterized histologically as papillary or follicular tumors. Although follicular cancers comprise only 10%–15% of thyroid cancers, they are of special interest for several reasons. First, it is not possible to distinguish follicular carcinomas from adenomas by biopsy. These tumors must be surgically removed to determine whether they are malignant, and approximately 80% of follicular neoplasms turn out to be benign. This situation contrasts with that for papillary thyroid cancers, which generally are straightforward to diagnose by fineneedle biopsy. Second, follicular thyroid cancers are more prone than papillary cancers to form distant (lung) metastases and are less prone to spread locally to neck lymph nodes. Thus, the detection of recurrences at an early, localized stage is more difficult. For both papillary and follicular thyroid cancers, there is no effective chemotherapy for patients not cured by the standard therapies of surgery and radioiodine. Thyroid cancers usually are associated with specific genetic abnormalities. For example, close to half of papillary carcinomas have an activating mutation of the kinase BRAF (1 ). Activating RAS mutations, or gene fusions that cause inappropriate activation of the RET tyrosine kinase, also occur in papillary carcinomas. All of these mutations cause activation of mitogen-activated protein kinase signaling. RAS mutations also are found in 30%– 40% of follicular thyroid carcinomas and adenomas. A similar fraction of follicular carcinomas, but a much smaller fraction of adenomas, are found to harbor a t(2;3)(q13; p25) chromosomal translocation that fuses the PAX8 (paired box 8) gene with the PPARG (peroxisome proliferator-activated receptor gamma) gene (2 ). PAX8 is a transcription factor that is produced in high amounts in the thyroid. It is required for thyroid gland development, and it induces the expression of many thyroid-specific genes. PPAR is a nuclear hormone receptor that plays important roles in carbohydrate and lipid metabolism, as well as in inflammation. It is produced at very low concentrations in the nonpathologic thyroid, however, and its function in this organ, if any, is unknown. The consequence of the t(2;3)(q13; p25) translocation is that the strong PAX8 promoter drives the production of a PAX8-PPAR fusion protein (PPFP). How PPFP contributes to thyroid neoplasia is not clear. Although PPFP can show dominant negative activity against PPAR in transfection experiments (2 ), evidence also suggests it can function in a PPAR like manner, both in transfection experiments and in thyroid cancer (3, 4 ). The ability to identify follicular thyroid tumors that produce PPFP is important for several reasons. Obviously, studying the mechanism of tumorigenesis and the biology of these cancers requires the ability to detect PPFP production and to compare PPFP-positive and -negative follicular cancers. The ability to detect PPFP also may have diagnostic importance, especially given that it is impossible to distinguish follicular carcinomas from adenomas by biopsy. In fact, this distinction can be difficult even in surgical samples. Although PPFP is occasionally found in follicular adenomas, it is many times more prevalent in follicular carcinomas. Furthermore, follicular adenomas with PPFP tend to have atypical features, such as increased proliferation