2q13

Thyroid tumors

PAX8/PPARgamma1 is an oncoprotein resulting from fusion of the DNA-binding domains of PAX8 to domains A to F of the peroxisome proliferator-activated receptor gamma-1 (PPARgamma1). It involves a chromosome 3p25 and 2q13 translocation, creating a fusion gene. This encompasses the promoter and the proximal coding portion of PAX8 gene and most of the coding sequence of the PPARgamma1 gene. PPARgamma1 maps to 3p25, which is a breakpoint hot spot region for thyroid tumors of follicular cell origin (follicular carcinomas and adenomas).

t(2;3)(q13;p25). Fine mapping and molecular characterization of the 2q13 and 3p25 translocation breakpoint regions revealed fusion between exons 1 to 7, 1 to 8, or 1 to 9 of PAX8 (2q13) and exons 1 to 6 of PPARgamma1 (3p25).

PAX8/PPARgamma1 (PPFP)

Translocations or inversions can give rise to the activation of an oncogene through its positioning near a strong promoter or its fusion with another gene, endowing the fused transcript with tumorigenic properties.
PAX8 is a transcription factor with a key role in the maintenance of a differentiated phenotype in thyroid follicular cells. PPARgamma is a ligand dependent nuclear transcription factor highly expressed in adipose tissue.
The PAX8 promoter, which is active in thyroid follicular cells, drives the expression of PAX8/PPARgamma1 fusion protein (PPFP). Since no point mutations in the PPARgamma1 gene have been found in thyroid carcinomas and cell lines, it is speculated that PPARgamma1 activation resulting from the rearrangement plays a direct oncogenetic role. Reduced expression of normal PAX8 protein may also contribute to tumor development. In fact, PPFP oncogenic effects could relate to constitutive overexpression of the full length PPARgamma1 domain, interference with wild-type PPARgamma1 or PAX8 function, novel intrinsic properties of PPFP, or a combination of the above. PPARgamma1 is thought to be the principal target of a class of antidiabetic agents (thiazolidinediones) and PPFP inhibits thiazolidinedione-induced gene transactivation by wild-type PPARgamma1. PAX8/PPARgamma1 has been identified in thyroid tumors of follicular cell derivation characterized by a well developed follicular pattern of growth. These tumors are usually follicular carcinomas but may also be follicular variant papillary carcinomas or follicular adenomas. It has therefore been suggested that PAX8/PPARgamma1 represents an early event in follicular cell tumorigenesis. Diagnosis of thyroid malignancies with a follicular growth pattern is primarily based on the identification of capsular or vascular invasion, which can only be assessed by histopathological examination of the surgically removed specimen. As a consequence, many individuals diagnosed with a follicular-patterned thyroid neoplasm undergo surgery. Since PAX8/PPARgamma1 is associated with a diagnosis of carcinoma, identification of the rearrangement may prove a useful tool for molecular diagnosis.

Thyroid follicular carcinoma

PAX8/PPARgamma1 has been identified in thyroid tumors of follicular cell derivation characterized by a well developed follicular pattern of growth. These tumors are usually follicular carcinomas but may also be follicular variant papillary carcinomas or follicular adenomas.

Thyroid follicular carcinoma is a malignant epithelial tumor showing evidence of follicular cell differentiation and lacking the diagnostic nuclear features of papillary carcinoma.

PAX8/PPARgamma1 is detected in ~30-40% of thyroid follicular carcinomas. Follicular carcinomas with PAX8/PPARgamma1 are angioinvasive and may be aggressive.

Papillary thyroid carcinoma, follicular variant

PAX8/PPARgamma1 has been identified in some papillary thyroid carcinomas, follicular variant (up to 30% in some series).

A malignant epithelial tumor showing evidence of follicular cell differentiation and characterized by distinctive nuclear features (enlargement, oval shape, elongation and overlapping). Follicular variant papillary carcinoma is composed of follicular structures without well developed papillae.

Thyroid follicular adenoma

PAX8/PPARgamma1 has been identified in ~5-10% of thyroid follicular adenoma.

A benign, encapsulated tumor of the thyroid showing evidence of follicular cell differentiation.

Thyroid follicular adenomas are benign tumors.

Wilms tumor

PAX8 is expressed in Wilms tumor and it is potentially involved in its induction. Pax-8 gene product resides upstream of wt1 in a common regulatory pathway. Two PAX8 isoforms, generated by alternative splicing at the C-terminus, were found to be capable of activating wt1 expression. PAX8 function during mesenchymal-epithelial cell transition in renal development is to induce wt1 gene expression.

Wilms tumor, or nephroblastoma, is a malignant embryonal neoplasm of the kidney derived from nephrogenic blastemal cells that replicate the histology of the developing kidney. The tumor often shows divergent differentiation patterns. It is characterized by abortive tubules and glomeruli, surrounded by a spindled cell stroma. The stroma may include striated muscle, cartilage, bone, fat tissue. The genes predisposing to Wilms tumor are WT1 and WT2.

Wilms tumor is aggressive but potentially curable.

Ovarian carcinoma

Aberrant transcriptional expression of PAX8 has been reported in epithelial ovarian cancer.

Malignant tumors of the ovary derived from the ovarian surface epithelium or its derivatives.

PAX8 (with PAX2) may be a candidate for the upregulation of WT1 in a proportion of Acute myeloid leukaemias.

Acute myeloid leukemia is a neoplasm of myeloid blasts in bone marrow, blood or other tissue.

Congenital hypothyroidism non-goitrous type 2 (CHNG2)

Several PAX8 mutations have been identified, located in the conserved paired domain of PAX8.

Congenital hypothyroidism non-goitrous type 2 (CHNG2) is a congenital form of hypothyroidism due to thyroid dysgenesis (athyreotic hypothyroidism), while congenital hypothyroidism non-goitrous type 1 (CHNG1) is due to resistance to thyroid-stimulating hormone (TSH).
Primary congenital hypothyroidism is usually sporadic but if caused by organification defects is often recessively inherited.
The mutant proteins have markedly reduced DNA binding with subsequent loss of transcriptional activation function. The mutations are thought to disrupt the pronounced gain of alpha helical PAX8 content that follows the interaction of PAX8 with DNA: they impair the unstructured to structured transition that occurs during DNA recognition (loss of "induced fit"). As a result of the mutations PAX8 protein cannot perform its role in activating transcription of its target-genes, such as TG, TPO and NIS.
Marked phenotypic variability has been found within affected families, suggesting variable penetrance and expressivity of PAX8 gene defects.
Some PAX8 mutations cause congenital hypothyroidism, while others mildly reduce thyroid hormone levels or have no detectable effect. Accordingly, thyroid glands of patients with PAX8 mutations are often small and hypoplastic, sometimes completely absent (athyreosis), supporting the concept that PAX8 mutations disrupt the normal growth and survival of thyroid cells during embryonic development. The reduced thyroid parenchymal mass may be unable to produce the required amounts of thyroid hormone. However, normal thyroid glands have also been reported in patients carrying PAX8 mutations. A small deletion (c.989_992delACCC) in exon 7 causing a frameshift with premature stop codon after codon 277 has been described in a patient with congenital hypothyroidism and thyroid hypoplasia.