Sporadic Thyroid Cancer Research Articles

Prevalence, Clinicopathologic Features, and Somatic Genetic Mutation Profile in Familial Versus Sporadic Nonmedullary Thyroid Cancer

Although hereditary nonmedullary thyroid cancer is recognized as a distinct and isolated familial syndrome, the precise prevalence and genetic basis are poorly understood. Moreover, whether familial nonmedullary thyroid cancer (FNMTC) has a more aggressive clinical behavior is controversial. The objectives of this study were to determine the prevalence of FNMTC, and compare the extent of disease and tumor somatic genetic alteration in patients with familial and sporadic papillary thyroid cancer. The main study entry criterion was patients who had a thyroid nodule that required a clinical evaluation with fine-needle aspiration biopsy and or thyroidectomy. A family history questionnaire was used to determine the presence of familial and sporadic thyroid cancer. Thyroid nodule fine-needle aspiration biopsy samples and tumor tissue at the time of thyroidectomy were used to test for somatic genetic mutations (BRAF V600E, NRAS, KRAS, NTRK1, RET/PTC1, and RET/PTC3). There were 402 patients with 509 thyroid nodules enrolled in the study. The prevalence of FNMTC was 8.8% in all patients with thyroid cancer and 9.4% in patients with only papillary thyroid cancer. None of the patients with FNMTC had another familial cancer syndrome. There was no significant difference in gender, tumor size, lymph node metastasis, and overall stage between sporadic and familial cases of thyroid cancer. Patients with FNMTC were younger at diagnosis than patients with sporadic papillary thyroid cancer (p < 0.002). Seventy-nine of the 504 thyroid nodules had somatic genetic mutations (29 BRAF V600E, 29 NRAS, 8 KRAS, 1 NTRK1, 4 RET/PTC1, and 8 RET/PTC3). There was no significant difference in the number or type of somatic mutations between sporadic and hereditary cases of papillary thyroid cancer. We found a higher prevalence of FNMTC in patients with papillary thyroid cancer than previously reported. Patients with FNMTC present at a younger age. Somatic mutations and extent of disease are similar in sporadic and FNMTC cases.

Clinical Characteristics and Outcome of Familial Nonmedullary Thyroid Cancer: A Retrospective Controlled Study

Familial nonmedullary thyroid cancer (FNMTC) is a disease defined by clustering of thyroid cancers of follicular cell origin, and it is estimated to account for 5% of all thyroid cancers. Several studies found FNMTC to be more aggressive than sporadic disease, whereas others found them to have a similar course and outcome. The purpose of this study was to determine whether FNMTC is more aggressive than sporadic thyroid cancer. A retrospective controlled study of FNMTC versus sporadic nonmedullary thyroid cancers was conducted using a registry of patients with thyroid cancer. Data on disease severity at presentation, treatment modalities, and outcome were collected. Sixty-seven patients with FNMTC and 375 controls with sporadic disease were included. Follow-up period was 8.6 ± 10 years for patients with FNMTC and 8.4 ± 9.1 years for sporadic cases. Patients with FNMTC had comparable disease severity at diagnosis as sporadic patients, underwent similar surgical and radioiodine treatments, and had similar long-term disease-free survival. Long-term outcome in families with three or more affected relatives was similar to families with only two affected relatives. Our results suggest that FNMTC is not more aggressive than sporadic thyroid cancer within our studied population. After a similar therapeutic strategy, FNMTC and sporadic cases had comparable prognosis, including in families with three or more affected members.

Abstract 3041: Differential expression of microRNAs between sporadic and hereditary nonmedullary thyroid cancer

Abstract Background: MicroRNAs (miRNAs) are small noncoding RNAs, which regulate gene expression and play a significant role in many biological processes, including tumorigenesis. Approximately 5% of all non-medullary thyroid cancers are hereditary and may have more aggressive tumor biology than sporadic cases. The susceptibility gene for hereditary non-medullary thyroid cancer has not been identified. We hypothesized that miRNA expression profile between sporadic and hereditary non-medullary thyroid cancer are different and could help identify candidate suspceptibility genes. Methods: Twenty nine tumor tissue samples were analyzed using miRNA microarrays for 1190 miRNAs with genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3) present in non-medullary thyroid cancer. The samples were matched for age, gender and stage of cancer. Differences in miRNA expression profile were validated by quantitative RT-PCR and correlated with clinicopathologic data. Results: We found 5 miRNAs significantly differentially expressed between sporadic and hereditary non-medullary thyroid cancer cases; two miRNAs were upregulated and three miRNAs were downregulated in hereditary non-medullary thyroid cancer. Two miRNAs were validated by quantitative RT-PCR; miR-20a (p=0.025) and miR-886-3p (p=0.028) were upregulated in hereditary non-medullary thyroid cancer samples. Higher expression level of miR-886-3p was significantly associated with higher TNM stage (p&amp;lt;0.05). There was no significant difference in somatic mutation rates between sporadic and hereditary cases (9 BRAF V600E, 1 RET/PTC1), and there was no significant difference in miR-20a and miR-886-3p expression by mutation status. Conclusions: To our knowledge, this is the first study to show different expression profile of miRNAs between sporadic and hereditary cancer using non-medullary thyroid cancer as a model. These differences in miRNAs may have an important role in tumor cell biology and clinical manifestation of non-medullary thyroid cancer in sporadic versus hereditary cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3041.

Allelic variant at −79 (C&gt;T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels

The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27(Kip1), are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (-79C>T) and rs36228499 (-838C>A)) to perform the first case-control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (-79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09-4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27(Kip1) promoter (P value <0.001). This effect was observed in -79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the -79C>T (rs34330) variant as a novel mechanism underlying p27(Kip1) downregulation.

Telomeres and thyroid cancer.

Telomeres are specialized structures at the ends of chromosomes, consisting of hundreds of repeated hexanucleotides (TTAGGG)n. Genetic integrity is partly maintained by the architecture of telomeres and it is gradually lost as telomeres progressively shorten with each cell replication, due to incomplete lagging DNA strand synthesis and oxidative damage. Telomerase is a reverse transcriptase enzyme that counteracts telomere shortening by adding telomeric repeats to the G-rich strand. It is composed of a telomerase RNA component and a protein component, telomerase reverse transcriptase. In the absence of telomerase or when the activity of the enzyme is low compared to the replicative erosion, apoptosis is triggered. Patients who have inherited genetic defects in telomere maintenance seem to have an increased risk of developing familial benign diseases or malignant diseases. At the somatic level, telomerase is reactivated in the majority of human carcinomas, suggesting that telomerase reactivation is a critical step for cancerogenesis.In sporadic thyroid carcinoma telomerase activity is detectable in nearly 50% of thyroid cancer tissues and some authors proposed that the detection of telomerase activity may be used for differentiating between benign and malignant thyroid tumours. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial papillary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer.In this report, we will review the role of telomere-telomerase complex in sporadic and familial thyroid cancer.

Sporadic and radiation-associated papillary thyroid cancers can be distinguished using routine immunohistochemistry

We investigated protein abundance in order to differentiate radiation-associated papillary thyroid cancers (PTC) from other etiologies for e.g. forensic purposes. Proteins were extracted from frozen tissues originating from 91 sporadic PTCs and 86 post-Chernobyl PTCs. Proteins were separated gel-electrophoretically, gels were silver stained, spots scanned and their intensity quantified. After excision of spots from the gel and protein digestion, MALDI-TOF mass spectrometry was performed followed by correlation of these results to human proteins using appropriate software and database. After this screening approach, altogether 20 candidate proteins were selected and measured semiquantitatively (Remmele score) using immunohistochemistry. Logistic regression modeling was performed for discriminating the groups. NTRK1, metalloproteinases (MMP-1, MMP-9 and MMP-13) and Cathepsins (-W and -X) proved to be of highest significance for discriminating the groups irrespective of the regression model utilized. When considering age and gender, each of 3 proteins by itself made possible a complete separation of the groups otherwise a combination of 2 of the 5 proteins mentioned was needed. In conclusion, abundance of proteins known to be associated with a more aggressive tumor type (MMPs and Cathepsins) appeared increased in post-Chernobyl PTC compared to sporadic PTC, thus underlining the known aggressiveness of radiation-associated PTC. These proteins make it possible to completely distinguish post-Chernobyl from sporadic PTC using routine immunohistology.

Genetic Aspects of Familial Thyroid Cancer

Familial thyroid cancer is rare, accounting for <10% of thyroid cancer cases. Activating germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia types 2A, 2B, and familial medullary thyroid cancer (FMTC)-around 3% of thyroid cancer cases. Familial papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) have been identified as a distinct group of familial thyroid cancers. Sporadic nonmedullary thyroid cancer (NMTC) accounts for approximately 90% of all thyroid cancers-about 6% of NMTCs are familial (FNMTC). Although multiple endocrine neoplasia types 2A and 2B and FMTC are well characterized, very little is known about the genetic predisposition to PTC and FTC. In this paper, the genetic types of FMTC and FNMTC are reviewed and the clinical features and screening are outlined.

Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity

Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.

Fine Needle Aspiration Analysis of B-RAF in Thyroid Nodules

Objective Fine needle aspiration (FNA) represents the most useful initial diagnostic tool with which to analyze thyroid nodules for carcinoma. A mutation of the B-type RAF kinase (BRAF) represents the most common genetic alteration in sporadic papillary thyroid cancer (PTC), and may signify a more aggressive biological behavior within PTCs. Our objective was to determine if BRAF analysis of FNA cytology may provide clinically useful information in the analysis of thyroid nodules. Methods An IRB-approved retrospective chart review of clinically relevant data for classic PTCs (CPTC), follicular-variant of PTC (FV-PTC), or non-malignant goiter was performed following a blinded pathologic re-review. Both pathologic and cytology samples were analyzed by fluorescent melting curve analysis (FMCA) for the V600E mutation of BRAF, and mutational status was compared with clinical information. Results A 100% concordance was found for BRAF mutation determination between the cytologic and final pathologic malignant and benign tissue samples studied. BRAF mutation was found to be significantly higher in papillary carcinomas when compared to follicular-variant of papillary thyroid carcinomas (55.6% vs. 14.3%, p=0.05), and correlated with cytologic interpretation (p=0.025) and histologic diagnosis (p=0.03). Conclusions FMCA of thyroid nodule FNAs can accurately determine the mutational status of the BRAF gene. Since the presence of BRAF mutation can predict a more aggressive biological behavior, an analysis of BRAF mutational status of initial FNAs may add useful information to the list of risk stratification criteria for PTCs.

Short Telomeres, Telomerase Reverse Transcriptase Gene Amplification, and Increased Telomerase Activity in the Blood of Familial Papillary Thyroid Cancer Patients

Differentiated papillary thyroid cancer is mostly sporadic, but the recurrence of the familial form has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer. The aim of our work was to study the telomere-telomerase complex in the peripheral blood of patients with familial papillary thyroid cancer (FPTC), including the measurement of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity, and search of hTERT or telomerase RNA component gene mutations. Cumulating a series of patients seen at the University of Siena and a series at the University of Rome, the experiments were conducted in 47 FPTC patients, 75 sporadic papillary thyroid cancer (PTC) patients, 20 patients with nodular goiter, 19 healthy subjects, and 20 unaffected siblings of FPTC patients. RTL, measured by quantitative PCR, was significantly (P < 0.0001) shorter in the blood of FPTC patients, compared with sporadic PTCs, healthy subjects, nodular goiter subjects, and unaffected siblings. Also by fluorescence in situ hybridization analysis, the results confirmed shorter telomere lengths in FPTC patients (P = 0.01). hTERT gene amplification was significantly (P < 0.0001) higher in FPTC patients, compared with the other groups, and in particular, it was significantly (P = 0.03) greater in offspring with respect to parents. hTERT mRNA expression, as well as telomerase activity, was significantly higher (P = 0.0003 and P < 0.0001, respectively) in FPTC patients, compared with sporadic PTCs. RTL, measured in cancer tissues, was shorter (P < 0.0001) in FPTC patients, compared with sporadic PTCs. No mutations of the telomerase RNA component and hTERT genes were found. Our study demonstrates that patients with FPTC display an imbalance of the telomere-telomerase complex in the peripheral blood, characterized by short telomeres, hTERT gene amplification, and expression. These features may be implicated in the inherited predisposition to develop FPTC.

A Radiation-Induced Gene Signature Distinguishes Post-Chernobyl from Sporadic Papillary Thyroid Cancers

We investigated selected gene targets to differentiate radiation-induced papillary thyroid cancers (PTCs) from other etiologies. Total RNA was isolated from 11 post-Chernobyl PTCs and 41 sporadic PTCs characterized by a more aggressive tumor type and lacking a radiation exposure history. RNA from 10 tumor samples from both groups was pooled and hybridized separately on a whole genome microarray for screening. Then 92 selected gene targets were examined quantitatively on each tumor sample using an RTQ-PCR-based low-density array (LDA). Screening for more than fivefold differences in gene expression between the groups by microarray detected 646 up-regulated and 677 down-regulated genes. Categorization of these genes revealed a significant (P < 0.0006) over-representation of the number of up-regulated genes coding for oxidoreductases, G-proteins and growth factors, while the number of genes coding for immunoglobulin appeared to be significantly down-regulated. With the LDA, seven genes (SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC and PAGE1) made a complete differentiation between the groups possible. Gene expression patterns known to be associated with a more aggressive tumor type in older patients appeared to be more pronounced in post-Chernobyl PTC, thus underlining the known aggressiveness of radiation-induced PTC. Seven genes were found that completely distinguished post-Chernobyl (PTC) from sporadic PTC.

BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma

BRAF(V600E) mutation represents the most common oncogenic event in sporadic papillary thyroid cancer (PTC). There are, however, significant discrepancies regarding the overall frequency, its prevalence in PTC-variants, and its relationship with clinico-pathological parameters of poor outcome. Moreover, the impact of BRAF(V600E) mutants on tumour-related patient's death has not been evaluated. We analysed, by PCR-SSCP and/or PCR-direct sequencing, exons 8, 10, 11 and 15 of BRAF in 113 tumour samples from 49 PTC-patients. Matched lymph node metastases and/or distant metastases (DMs) were screened in 35 patients. Focal changes in the growth pattern or microscopic grade within the primary tumour (Pt) or the metastases were separately genotyped. Mutations at H-, K-, N-ras and PIK3CA exons 9 and 20 were also investigated. For comparison with PTC cases, the BRAF and Ras mutational status was evaluated in 89 specimens obtained from 24 poorly differentiated thyroid carcinomas (PDCs) and 36 anaplastic thyroid carcinomas (ATCs). BRAF(V600E) was found in 13/16 classical PTCs (CL-PTCs), 6/17 follicular variant PTCs (FV-PTCs) and 8/16 mixed (papillary/follicular) PTCs (Mx-PTCs), being significantly associated with CL-PTCs (P = 0.015). BRAF(V600E) segregated with metastatic PTC-cells in 43% of the patients, but only one DM disclosed the mutation. PTC-tumours featuring concurrent less-differentiated foci were BRAF wild-type in both components. Noteworthy, the frequency of BRAF mutations among PDCs and ATCs resulted considerably lower (16.6% and 25%, respectively) than in PTCs (55%). The prevalence of Ras mutations among PDCs and ATCs (46% and 36%, respectively) was, however, much higher than in PTCs (14%). Five (71%) of the patients who died of PTC displayed somatic mutations. Four of them had other gene alteration associated with BRAF(V600E) and the only one that did not, BRAF(V600E) was restricted to the Pt. The occurrence of BRAF(V600E) associated with other genetic events was an independent predictor of DMs during follow-up, recurrence and tumour-related death. Remarkably, two PDCs (8.3%) and five ATCs (14%) revealed concurrent BRAF and Ras mutations. BRAF(V600E)'alone' does not represent a marker for poor outcome, however, when associated with alterations in other genes identifies a subset of PTCs with increased risk of recurrence and decreased survival.

Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers

Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, γ-radiation and H2O2. On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to γ-radiation and H2O2 are similar. On a finer scale, a 118 genes signature discriminated the γ-radiation and H2O2 responses. This signature could be used to classify the tumours as CTB or French with an error of 15–27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to γ-radiation and H2O2. These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test.

An Evidence‐based Approach to Familial Nonmedullary Thyroid Cancer: Screening, Clinical Management, and Follow‐up

Approximately 5% of nonmedullary thyroid cancers are of familial origin. When two or more family members are diagnosed with nonmedullary thyroid cancer in the absence of other known associated syndromes it is termed familial nonmedullary thyroid cancer (FNMTC). The genetic inheritance of FNMTC remains unknown, but it is believed to be an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity. FNMTC has been shown to be more aggressive and to have a worse prognosis than sporadic nonmedullary thyroid cancer. For example, studies have demonstrated that individuals with FNMTC have an increased risk of multifocal disease, local invasion, and lymph node metastases. These aggressive features appear to contribute to the higher recurrence rate and decreased disease-free survival seen in FNMTC patients compared to those with sporadic differentiated thyroid cancer. This article is an overview of the literature available in the English language discussing FNMTC. Critical questions regarding the screening, management, and follow-up of these patients are addressed with answers proposed based on the available literature. The quality of the evidence is ranked according to Sackett's criteria. Overall, the literature quality is somewhat limited, based on the low prevalence of FNMTC, the difficulty in identifying familial cases, the variable study designs, and limited long-term follow-up. To date, the optimal clinical approach is yet to be established, but improved awareness and screening will permit earlier detection, more timely intervention, and hopefully improved outcomes for patients and their families.

Childhood thyroid cancer in Belarus

The retrospective analysis was performed to compare the clinical course of radiogenic and sporadic childhood thyroid cancer. The entire series included 752 patients aged less than 15 years at diagnosis. Of them, 686 (91.2%) individuals had radiation history including 681 (90.6%) exposed at the time of the Chernobyl disaster and 5 (0.7%) children were previously treated for malignant lymphoma with an external beam therapy. The second group consisted of 66 (8.8%) unexposed patients. All the children underwent surgery and received suppressive thyroxine therapy with the mean dose of 2.0–2.5 μg/kg of body weight. Radioiodine therapy was performed in 464 (61.7%) cases. The comparison of patients with radiogenic and sporadic thyroid cancer did not reveal statistically significant differences in the distribution of tumor size, histological type or TNM stage. During follow-up time relapses were registered in 204 (27.1%) patients. The main sites of recurrence were the lung or lymph nodes whereas other lesions (thyroid remnants, the bone, soft tissues or CNS involvement) were uncommon. The disease-free survival ranged widely, 0–213 months after the date of primary surgery without significant difference between the radiogenic and sporadic cases. The observed 10-year survival was 99.5% for the entire series, including 99.5% and 99.7% in patients with radiogenic and sporadic carcinomas, respectively.

RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy

A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.

Polymorphic ATM gene variants in radiation-induced and sporadic papillary thyroid cancer in children

Polymorphic ATM gene variants in radiation-induced and sporadic papillary thyroid cancer in children

Disparities between male and female patients with thyroid cancers: sex difference or gender divide?

This investigation was undertaken to quantify histopathological disparities between male and female patients with sporadic and hereditary thyroid cancers, which may reflect a biological 'sex difference' or a behavioural 'gender divide'. Retrospective cohort analysis (November 1994-January 2006). 1298 Consecutive surgical patients with sporadic papillary (n = 587), sporadic follicular (n = 232), sporadic medullary (n = 320), and hereditary medullary thyroid cancers (n = 159) from a tertiary referral centre. Age at diagnosis of cancer, primary tumour diameter, frequency of extrathyroidal extension, lymph node and distant metastases, and cancer subtypes. Primary diameters of sporadic tumour entities (papillary, 26.0 vs. 19.3 mm; follicular, 54.9 vs. 35.1 mm; and medullary, 27.9 vs. 20.8 mm), but not hereditary medullary cancers, were significantly (P <or= 0.001) larger in male patients. Likewise, lymph node metastases from sporadic papillary cancers (60%vs. 44%, P < 0.001), the insular subtype in sporadic follicular cancers (22%vs. 8%, P = 0.003), extrathyroidal extension of sporadic medullary cancers (35%vs. 15%, P < 0.001), and distant metastases from sporadic medullary cancers at the most recent operation (29%vs. 15%, P = 0.002) were seen significantly more often with male patients. No significant differences were observed between male and female patients with hereditary medullary cancers, half of which were detected by screening. Our data emphasize the need for earlier diagnosis and intervention in male patients to ensure that male sex will cease sometime to constitute an ominous prognostic marker of advanced thyroid cancer.

Clinical and Genetic Aspects of Sporadic Non-Medullar Thyroid Cancer

The role of somatic mutations in sporadic thyroid cancer is unclear today. Probably they coming out as aetiological factors in carcinogenesis as well as, respectfully to many authors, can to participate in TC pathogenesis and to determine the clinical course and prognosis of the disease. For today as main oncogenes taking part in initiation of thyroid malignant tumors are considered: RET/PTC, TRK, PTEN, P53, RAS, MET, PPARγ. By means of genetic investigations scientists are trying to solve problems with thyroid cancer differentiated diagnostics (cytokeratin-19, cytokeratin-20, mesothelial cells antigen (Hector Battifora MEsotelial (cell) or HBME-1), loss of heterozigitoty (LOH) in short arm of 3 chromosome (gene VHL -von Hippel Lindau, 3р26). Recently in foreign literature appeared reports of activated mutations in gene BRAF which most frequently are occurred in melanoma and papillary TC. Prognosis of thyroid cancer may reflected by the LOH as a biological breakage as well as changes of tumor suppressive gene P53 which fraught with decrease of disease prognosis. Thus, both researchers and clinicians have many questions concerning the role of genome, particularly in order to precise of genetic abnormality influence on tumor growth and therefore for assessment of clinical prognosis and with aim to chose adequate treatment tactic in each case.

Does Familial Non‐Medullary Thyroid Cancer Adversely Affect Survival?

Familial non-medullary thyroid cancer (FNMTC) is associated with a higher rate of multifocality and a higher recurrence rate than sporadic thyroid cancer. However, the effect of FNMTC on life expectancy is unknown. Using data from our FNMTC database, we calculated life expectancy and survival rates after diagnosis of FNMTC and compared the results with the rates for unaffected family members and for the standard US population. Overall life expectancy and survival rates were calculated using the Kaplan-Meier method. We compared patients from families with 2 affected members with patients from families with > or = 3 affected members. We also compared patients diagnosed in a known familial setting (index cases and subsequent cases) with patients diagnosed before the familial setting was recognized. There were 139 affected patients with 757 unaffected family members. The mean age at diagnosis was 40.8 +/- 13.9 years and the mean follow-up time was 9.4 +/- 11.7 years. Ten patients died of thyroid cancer during follow-up. The life expectancy of patients with FNMTC was similar to that of their unaffected family members. Survival was significantly shorter for patients with 3 or more affected family members, for patients diagnosed before the familial setting was recognized, and for patients with anaplastic cancer. Our results suggest that FNMTC may be more aggressive than sporadic thyroid cancer, particularly in families with 3 or more affected members. However, when recognized and treated appropriately, it does not significantly shorten the overall life expectancy of the affected patients.