Oncogenesis in Thyroid Cancers of Follicular Cell Origin

Oncogene Receptor Proteins

THYROID-STIMULATING HORMONE RECEPTOR

The thyroid-stimulating hormone (TSH) receptor is a transmembrane glycoprotein that is G protein coupled. TSH, acting through its receptor, is the main regulator of thyro-cyte function and growth. Its function is mediated via the adenylate cyclase and phospholipase C intracellular pathways.5 Constitutively activating mutations in the TSH receptor occur in the transmembrane segment and intracy-toplasmic loop in hot thyroid nodules (=30%) but are usually absent in cold thyroid nodules or thyroid cancers (Table 31-1).510 Unfortunately, the frequency of TSH receptor-activating mutations observed in hot thyroid nodules has been variable, ranging from 3% to 82%.5-12 This discrepancy is likely due to several factors such as small sample size, screening of only part of the TSH receptor gene, less sensitive screening techniques (single-strand conformation polymorphism), inaccurate characterization of thyroid nodule function, and the quality of DNA in tissue samples studied.12 In general, TSH receptor-activating mutations lead to some benign hot nodules but not to malignant thyroid neoplasms or cold thyroid nodules.13

Dormant

Apoptosis

2. External and endogenous growth stimuli

0 Dormant Q Apoptosis

"Late"

mutations { I)

Mitosis, accumulation of genetic alterations leading to unregulated proliferation and differentiation

Progression from normal cell toward a dedifferentiated state and uncontrolled growth

Progression from normal cell toward a dedifferentiated state and uncontrolled growth

Growth factors and signal transduction protein also influence the initiation and/or progression of thyroid neoplasm

EG F

TGFp

FIGURE 31-1. A, General multistep theory of genetic alterations in carcinogenesis. B, The genetic events that occur in thyroid oncogenesis (the main genetic events are in bold). The dashed lines for each histologic type of thyroid cancers indicate that an adenoma-to-carcinoma progression is not necessarily always the sequence of progression in carcinogenesis. PTC = papillary thyroid carcinoma; FTC = follicular thyroid carcinoma; HCC = Hiirthle cell carcinoma; EGF = epidermal growth factor; TGFp = transforming growth factor beta; IGF = insulin-like growth factor; TSH-R = thyroid-stimulating hormone receptor.

TABLE 31-1. Main Genes Involved in Thyroid Oncogenesis: Classification, Tumor Types, and Prevalence

Genes

Histologic Type

Prevalence

Comment

Receptor

RET/PTC

Met c-erb-2

Autonomous follicular adenoma PTC

PTC, FTC

Signal Transduction Proteins ras PTC, FTC, HCC, autonomous follicular adenoma gsp Autonomous follicular adenoma

Tumor Suppressor Genes and Nuclear Oncogenes

PAX8/PPARy FTC

PTEN

Poorly DTC, ATC

Benign follicular adenoma, infrequently in DTC

2,5-85%, higher with radiation exposure

26% of benign, 6% of malignant

TSH activation mutations are not oncogenic

Tyrosine kinase receptor, somatic mutation absent in benign thyroid neoplasms Tyrosine kinase receptor, somatic mutation Higher prevalence in radiation exposure Possibly associated with more aggressive tumors Five chimeric subtypes have been identified Tyrosine kinase receptor, somatic mutation Possibly associated with aggressive tumors Overexpressed mostly in PTC and poorly differentiated DTC Tyrosine kinase activity, similar to epidermal growth factor receptor Although overexpressed in PTC, the oncogene is not overamplified

Early event in carcinogenesis

May be associated with aggressive PTC

Early event in carcinogenesis Similar frequency in benign and malignant thyroid neoplasms Coexisting ras and gsp mutations in same tumor may be associated with aggressive DTC

The presence of this fusion oncoprotein may be used to differentiate follicular adenoma from carcinoma p63 immunohistochemistry may be predictive of tumor aggressiveness Thought to occur as a late genetic event in thyroid carcinogenesis Higher rate in benign than malignant tumor questions the presence of a strict adenoma to carcinoma sequence

PTC = papillary thyroid cancer; FTC = thyTOid cancer.

follicular thyroid cancer; HCC = Hiirthle cell carcinoma; DTC = differentiated thyroid cancer; ATC = anaplastic

Tyrosine Kinase Receptors

Tyrosine kinase receptor proteins are a well-recognized group of oncoproteins that are implicated in several human cancers and include almost 50 receptor proteins. The tyrosine kinase genes classically encode a transmembrane receptor protein. Ligand binding to the tyrosine kinase leads to activation, dimerization of the receptors, and then transphosphorylation of tyrosine kinase residues, with downstream activation of the tyrosine kinase genes. Several tyrosine kinase gene alterations are implicated in thyroid carcinogenesis; RET/PTC, TRK, c-erb-2 and met activate thyrocyte growth through a cyclic adenosine monophosphate-independent system.

RET/PTC ONCOGENE

The RET/PTC protooncogene maps to chromosome lOql 1.2, and five activating chromosomal rearrangements have been characterized.1415 The RET/PTC chimeric genes have been designated RET/PTC 1 to RET/PTC5.1- Permanent activation of the tyrosine kinase results from the 5' foreign genes.16 The five foreign genes fused to the RET tyrosine kinase domain occur almost exclusively in papillary thyroid cancer (see Table 31-1). The frequency of RET/PTC activating somatic mutations in sporadic papillary thyroid cancer is variable, ranging from 2.5% to 85%.2-17"30 This wide range in the prevalence of the RET/PTC rearrangement genes in papillary thyroid cancer may be due to geographic variation, the age of patients studied, or the sensitivity of experimental techniques employed or a consequence of ionized radiation or external radiation exposures.15 31 For example, in thyroid neoplasms associated with the Chernobyl accident, 55% to 85% of the thyroid cancers had RET/PTC rearrangement oncogenes, and only a few were observed in follicular adenoma.19'21,23'26 RET/PTC3 was the most common rearrangement identified in association with radiation exposure.16-23 The reason for the difference in distribution of the RET/PTC

chimeric subtype genes and its relation to radiation exposure remains unclear. The RET/PTC rearrangement genes have been identified in occult papillary thyroid cancer; therefore, it is considered to be an early event in the formation of papillary thyroid cancer.27 Some investigators have found that the presence of RET/PTC in patients with papillary thyroid cancer is associated with young age, radiation exposure, and lymph node metastasis but not distant metastasis.17-26-28-29

TRK ONCOGENE

The TRK protooncogene is located on chromosome lq21-22.32 TRK encodes for the receptor for nerve growth factor and results from chromosomal rearrangements.32"34 This chimeric gene is ubiquitously expressed and results in a constitutively activated tyrosine kinase protein. Four chimeric genes have been identified: three intrachromosomal rearrangements (TRK, TRK-T1, and TRK-T2) and one interchromosomal rearrangement (TRK-T3). The TRK protooncogene occurs infrequently in papillary thyroid cancer (6% to 20%) and has been detected in patients with and without radiation-associated papillary thyroid cancers (see Table 31 -l).32 34

MET ONCOGENE

Hepatocyte growth factor (scatter factor) binds the MET transmembrane tyrosine kinase receptor.35 Activation of the MET receptor promotes a mitogen response, cellular motility, and cellular invasion.35,36 In normal cells, MET activation is a ligand-dependent transient event, whereas in tumor cells MET activity is often constitutively upregulated.35'37 MET is overexpressed in about 75% of papillary thyroid cancers and poorly differentiated cancer and in only 22% of follicular thyroid cancers.38"40 MET overexpression may be associated with tumor multicentricity and less tumor angio-genesis in papillary thyroid cancer.3940 In contrast, absent or low MET expression in papillary thyroid cancer has been associated with a higher risk of distant metastasis.41 Although results are discrepant, it is possible that MET plays a role in the progression of thyroid cancers to an aggressive phenotype and probably occurs as a late event, because MET is overexpressed in more aggressive thyroid cancers.38-41-42

c-erb-2 ONCOGENE

The c-erb-2 oncogene (also referred to as HER and neu) encodes a transmembrane glycoprotein with tyrosine kinase activity.43 This epidermal growth factor (EGF) receptor-related protein is truncated and has been demonstrated to be predictive of prognosis in several human cancers.44-45 Because EGF, acting through the EGF receptor, is an important regulator of thyroid cell growth, several groups have studied c-erb-2 oncoprotein expression in thyroid cancers.45"48 The role of c-erb-2 in thyroid tumorige-nesis is controversial. Some investigators have found that the c-erb-2 protein is overexpressed in papillary thyroid cancer but not detected in follicular adenoma, follicular carcinoma, medullary carcinoma, and anaplastic carcinoma.47 Overamplification or rearrangement of the c-erb-2 oncogene has not been demonstrated in either benign or malignant thyroid neoplasms.47-48 Therefore, it remains to be determined if the c-erb-2 oncoprotein is an important factor in thyroid tumorigenesis.

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