Introduction

The Natural Thyroid Diet

The Natural Thyroid Diet

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The analyses of human thyroid tumor tissues have proven informative in identifying key molecular events in epithelial neoplasia. The thyroid gland gives rise to a variety of epithelial tumors that differ markedly in their biologic patterns. The accessibility of thyroid tumors provides a tractable opportunity to define mechanisms of epithelial cell transformation in a spectrum of related cancers.

Two primary issues must be considered when investigating molecular genetic alterations within human thyroid tumor groups. The first is tumor classification. Thyroid tumors are classified predominantly on the basis of morphologic features interpreted by pathologists. Morphologic features provide initial biologic and clinical information but they have been defined somewhat non-specifically in retrospective series. Thus, thyroid tumor diagnosis can be imprecise [1-4] and can create confusion when correlating molecular genetic alterations with clinical and pathologic features. Mutations that predominate in one thyroid tumor group may be identified in others and the distinction as to whether such tumors are misclassified or contain additional alterations is difficult to ascertain. A second important issue relates to mutation detection. Polymerase chain reaction-based amplification and sequencing of nucleic acids from fresh or fast-frozen tissues are most often employed. Such assays are exquisitely sensitive and prone to cross-contamination, particularly when poorly preserved or archival tissues are used. Polymerase chain reaction can even detect genetic alterations within a minute sub-fraction of tumor cells. The biologic significance of this is often unclear. Tissue

Figure 1. Histologic-Molecular Model of Thyroid Cancer Formation. Four main types of thyroid carcinoma with distinct biologic features are recognized. A subset of each type may progress to poorly differentiated and/or clinically aggressive forms. Genetic alterations that characterize these pathways and sub-pathways are shown.

Figure 1. Histologic-Molecular Model of Thyroid Cancer Formation. Four main types of thyroid carcinoma with distinct biologic features are recognized. A subset of each type may progress to poorly differentiated and/or clinically aggressive forms. Genetic alterations that characterize these pathways and sub-pathways are shown.

composition must also be documented rigorously because thyroid tumor resections contain admixtures of tumor, normal thyroid, lymphoid, reactive and stromal elements. All such factors must be considered or erroneous results will be obtained [5-7].

This chapter begins with a histologic-molecular model of thyroid cancer formation and discusses known mutations and emerging biologic and clinical correlates in follicular thyroid tumors. A summary and comparison of thyroid carcinomas with the acute myeloid leukemias follows.

A histologic-molecular model of thyroid cancer

A model that encompasses histologic, molecular, and biologic facets of thyroid cancer formation is shown in Figure 1. At least four sub-types of thyroid cancer with distinct characteristics are recognized. Tumors within each group may progress to poorly differentiated, metastatic, and/or anaplastic forms. The thyroid carcinoma model seems unique relative to other carcinomas in several respects. First, distinct gene mutations define separate pathways of oncogenesis within the thyroid. This is different than a single linear genetic pathway envisioned commonly for other carcinomas such as those arising in the colon [8] and exocrine pancreas [9, 10]. Second, both thyroid specific and non-thyroid specific mutations characterize different thyroid carcinoma subgroups. One particularly interesting class of thyroid-specific mutations is the chromosomal rearrangements that encode gene fusions [11, 12]. Gene fusions been identified infrequently in carcinomas even though they are common in blood cell and soft connective tissue cancers [13]. Third, thyroid cancer mutations correlate with specific biologic properties. For example, RET and PPARy rearrangements characterize papillary [14] and follicular [12] thyroid carcinomas that tend to spread via regional lymphatics or blood vessels, respectively. Distinct RET germ line point mutations identify different familial medullary thyroid carcinoma patients with propensities for poor outcome and/or concomitant non-thyroid disease [15]. Thus, mutation staus provides predictive biologic information in thyroid cancer and thus may augment our current morphology-based classification and treatment schemes. Even so, it must be kept in mind that a combination of cellular events, not single gene alterations, determines overall thyroid cancer biology. Thyroid tumors with apparently identical single gene mutations but distinct patterns of growth and/or prognoses have been reported [16-21].

PPARy rearrangements

Somatic rearrangements in the gene encoding the nuclear receptor have been identified in thyroid cancers with follicular cell differentiation, frequent encapsulation, vascular invasion and capsular penetration. These are follicular thyroid carcinomas (Figure 1). The discovery of PPARy rearrangements resulted from mapping [12] of a chromosomal translocation, t(2;3)(q13;p25), which had been identified in follicular thyroid tumors [12, 22-27]. The t(2;3) rearrangement juxtaposes the promoter region and 5' coding sequence of the PAX8 gene on chromosome 2 with most of the coding sequence of the gene on chromosome 3 and results in expression of a chimeric transcription factor (Figure 2).

is a thyroid-specific mutation and one member of a family of rearrangements in follicular carcinomas. Another follicular carcinoma translocation, t(3;7)(p25;q31) [28], fuses the promoter and 5' coding sequence of a novel transcription factor gene termed CREB3L2 or BBF2H7 [29] on chromosome 7 with most of the coding sequence of PPARy (Figure 2). PAX8-PPARy and CREB3L2-PPARy (Figure 2) contain identical PPARy sequences that include wild-type PPARy DNA binding, ligand binding, RXR dimerization, and transactivation domains [30]. Additional putative rearrangements have been detected in other follicular carcinomas [12, 22, 31, 32], rearrangements have been identified in 25-35% of follicular carcinomas based on studies using pathologically well-defined tissues [32-38]. rearrange ments [32] or RAS gene point mutations but not both [33] are detected early in low stage follicular carcinomas, suggesting the existence of sub-pathways of oncogenesis in follicular carcinoma (Figure 1). Such a model is further supported by distinct patterns of galectin-3 and HBME-1 protein expression in PPARy rearrangement- versus RAS mutation-positive follicular carcinomas [33] and by an additional genetic subset of follicular carcinomas (25%) that possess 3p25 aneusomy in the absence of rearrangement [32].

The mechanisms through which rearrangements deregulate thyrocyte growth are being investigated and aberrations in transcription (Figure 3) and other cell functions may be involved. PAX8-PPARy stimulates proliferation, inhibits apoptosis, and induces anchorage independent growth of human thyroid cells [39], supporting a primary role for in follicular cell transformation. also transforms NIH3T3 mouse fibroblasts in colony assays [39], demonstrating thatPAX8-

can alter both thyrocyte and non-thyrocyte growth functions. has little ability to stimulate transcription from response elements in vitro and also inhibits transcription mediated by wild-type PPARy [12, 39], activities that fit

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