Sporadic Thyroid Research Articles

Diverse phenotype of Ménière’s disease associated with family history, thyroid disorder, migraine and associated disorders

ObjectiveTo better understand the clinical phenotype of Ménière’s disease (MD), we examined family history, thyroid disorder, migraine, and associated disorders in complaints of people living with MD. MethodWe designed the study as a retrospective and examined data gathered from 912 participants with MD. Their data were originally collected by the Finnish Ménière Federation (FMF). The survey data included individual case histories for environmental factors, comorbidities, disease-specific complaints, impact-related questions, cognitive complaints, health-related quality of life (HRQoL), and sense of coherence (SOC). ResultsWe observed significant differences between those with and without sporadic occurrence, family history, thyroid disorder, and migraine-associated complaints. Family history explained 20% of variability in patient complaints. Patients with a family history of MD whose disease started at younger age experienced balance problems, more severe vertigo spells, more severe vestibular drop attacks (VDA), and less nausea, although they had good SOC. Thyroid disorder explained 14% of variability in patient complaints. MD patients with a thyroid disorder comorbidity suffered more often from constant dizziness, balance problems, greater impact of hearing problems, cognitive complaints, and poor HRQoL. Migraine explained 12% of variability in patients’ complaints and was associated with poor SOC and cognitive balance problems. MD patients with both thyroid disorder and migraine used antidepressants more often than other groups. Logistic regression analysis showed comorbidities of ischemic brain disorder (among 7.1%), kidney insufficiency (among 1.2%), and diabetes (among 7.3%) had statistically significant but restricted association with balance and gait problems, VDA, and reduced HRQoL. ConclusionsFamily history of MD and thyroid disorder or migraine comorbidities in MD influence the complaint pattern and partially explain complex symptom profiles, including symptoms of cognitive problems. Confounders play a minimal role in complaint profile and impact of MD whereas comorbidities influence the complaint structure and partly explain the complex symptom profile in MD.

The Genomic Landscape of Benign and Malignant Thyroid Tumors from Individuals Carrying Germline PTEN Variants Is Distinct from Sporadic Thyroid Cancers.

Exome sequencing reveals the distinct mutational landscape of PTEN hamartoma tumor syndrome-associated thyroid cancers from sporadic counterparts, providing insights into tumor progression and behavior that could help improve diagnosis, surveillance, and treatment.

Studies on surgical methods for sporadic micromedullary thyroid carcinoma

Abstract Background To observe the changes in serum calcitonin levels after application of different surgical methods for primary medullary thyroid microcarcinoma (MTMC) and explore a more reasonable surgical method. Methods A retrospective analysis of 36 patients with MTMC, 16 in group A and 20 in group B, was performed. In group A, tumors were single and confined to the thyroid lobe, and thyroid lobectomy with isthmusectomy was performed. In group B, tumors were in the isthmus or invaded the thyroid gland, or there were multiple foci in bilateral lobes, and patients with primary foci underwent total thyroidectomy. The median follow-up time was 3.6 years. Clinical and pathological characteristics and changes in serum calcitonin (CTn) and carcinoembryonic antigen levels after the surgery were compared between the 2 groups. Results The difference in the biochemical cure rate after surgery was statistically significant between patients with preoperative serum calcitonin levels <150 pg/mL and ≥150 pg/mL (P < 0.01). No significant differences in the biochemical cure rates and serum calcitonin levels were noted at different time points after surgery between group A and group B (P > 0.05). One recurrence and metastasis were observed in each group after surgery. Conclusions After performing different surgical methods for the primary foci of MTMC, the changes in serum calcitonin and carcinoembryonic antigen levels are similar. Especially for patients with single foci confined to the thyroid lobe without lateral cervical lymph node metastasis and with serum calcitonin levels <150 pg/mL, the unilateral thyroid lobectomy with isthmectomy can achieve the same therapeutic effect and biochemical cure rate as total thyroidectomy.

Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma.

Background: Familial non-medullary thyroid carcinoma (FNMTC) is a genetically predisposed disease with unclear genetic mechanisms. This makes research on susceptibility genes important for the diagnosis and treatment options. Methods: This study included a five-member family affected by papillary thyroid carcinoma. The candidate genes were identified through whole-exome sequencing and Sanger sequencing in family members, other FNMTC patients, and sporadic non-medullary thyroid carcinoma patients. The pathogenicity of the mutation was predicted using in silico tools. Cell phenotype experiments in vitro and models of lung distant metastasis in vivo were conducted to confirm the characteristics of the mutation. Transcriptome sequencing and mechanistic validation were employed to compare the disparities between PAK4 wild-type (WT) and PAK4 mutant (MUT) cell lines. Results: This mutation alters the protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding, and phosphorylation sites. It specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines. Compared with the WT cells line, PAK4 I417T demonstrates enhanced proliferation, invasiveness, accelerated cell division, and inhibition of cell apoptosis in vitro. In addition, it exhibits a significant propensity for metastasis in vivo. It activates tumor necrosis factor signaling through increased phosphorylation of PAK4, JNK, NFκB, and c-Jun, unlike the WT that activates it via the PAK4-NFκ-MMP9 axis. In addition, PAK4 MUT protein interacts with matrix metalloproteinase (MMP)3 and regulates MMP3 promoter activity, which is not observed in the WT. Conclusions: Our study identified PAK4: c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of PAK4 exhibits oncogenic function, suggesting its potential as a novel diagnostic molecular marker for FNMTC.

Clinical relevance and outcome of familial papillary thyroid cancer: a single institution study of 626 familial cases.

Whether familial thyroid cancer is more aggressive than sporadic thyroid cancer remains controversial. Additionally, whether the number of affected family members affects the prognosis is unknown. This study focused mainly on the comparison of the clinicopathological characteristics and prognoses between papillary thyroid cancer (PTC) patients with and without family history. A total of 626 familial papillary thyroid cancer (FPTC) and 1252 sporadic papillary thyroid cancer (SPTC) patients were included in our study. The clinical information associated with FPTC and SPTC was recorded and analyzed by univariate analysis. Patients in the FPTC group had a higher rate of multifocality (p=0.001), bilaterality (p=0.000), extrathyroidal invasion (p=0.000), distant metastasis (p=0.012), lymph node metastasis (p=0.000), recurrence (p=0.000), a larger tumor size (p=0.000) and more malignant lymph nodes involved (central: p=0.000; lateral: p=0.000). In addition, our subgroup analysis showed no significant difference (p>0.05) between patients with only one affected family member and those with two of more group in all clinicopathological characteristics. In papillary thyroid microcarcinoma (PTMC) subgroup analysis, we found that FPTMC patients harbored significantly larger tumors (p=0.000), higher rates of multifocality (p=0.014), bilaterality (p=0.000), distant metastasis (p=0.038), lymph node metastasis (p=0.003), greater numbers of malignant lymph nodes (central: p=0.002; lateral: p=0.044), higher rates of I-131 treatment (p=0.000) and recurrence (p=0.000) than SPTMC patients. Our results indicated that PTC and PTMC patients with a positive family history had more aggressive clinicopathological behaviors, suggesting that more vigilant screening and management for FPTC may be helpful.

DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer.

DICER1 is a highly conserved RNase III endoribonuclease essential for the biogenesis of single-stranded mature microRNAs (miRNAs) from stem-loop precursor miRNAs. Somatic mutations in the RNase IIIb domain of DICER1 impair its ability to generate mature 5p miRNAs and are believed to drive tumorigenesis in DICER1 syndrome-associated and sporadic thyroid tumors. However, the DICER1-driven specific changes in miRNAs and resulting changes in gene expression are poorly understood in thyroid tissue. In this study, we profiled the miRNA (n=2,083) and mRNA (n=2,559) transcriptomes of 20 non-neoplastic, 8 adenomatous and 60 pediatric thyroid cancers (13 follicular thyroid cancers [FTC] and 47 papillary thyroid cancers [PTC]) of which 8 had DICER1 RNase IIIb mutations. All DICER1-mutant differentiated thyroid cancers (DTC) were follicular patterned (six follicular variant PTC and two FTC), none had lymph node metastasis. We demonstrate that DICER1 pathogenic somatic mutations were associated with a global reduction of 5p-derived miRNAs, including those particularly abundant in the non-neoplastic thyroid tissue such as let-7 and mir-30 families, known for their tumor suppressor function. There was also an unexpected increase of 3p miRNAs, possibly associated with DICER1 mRNA expression increase in tumors harboring RNase IIIb mutations. These abnormally expressed 3p miRNAs, which are otherwise low or absent in DICER1-wt DTC and non-neoplastic thyroid tissues, make up exceptional markers for malignant thyroid tumors harboring DICER1 RNase IIIb mutations. The extensive disarray in the miRNA transcriptome results in gene expression changes, which were indicative of positive regulation of cell-cycle. Moreover, differentially expressed genes point to increased MAPK signaling output and loss of thyroid differentiation comparable to the RAS-like subgroup of PTC (as coined by The Cancer Genome Atlas), which is reflective of the more indolent clinical behavior of these tumors.

FAMILIAL NON-MEDULLARY THYROID CARCINOMA.

Familial non-medullary thyroid carcinoma (FNMTC) is defined as cancer developing in two or more first-degree relatives if predisposing factors, for example, radiation, are absent. The disease can be either syndromic, when it is a component of complex genetic syndromes, or non-syndromic (95% cases). The genetic basis of non-syndromic FNMTC is unknown; the clinical behavior of tumorsis unclear and, at times, contradictory. To analyze clinical manifestations of FNMTC and compare them with the data for sporadic papillary thyroid carcinomas in patients of the same age groups. We examined 22 patients (a "parents" group and a "children" group) suffering from the non-syndromic FNMTC. For comparison, two groups of sporadic papillary carcinomas patients of the same age were drawn up("adult" and "young"). We analyzed tumor size and frequency of the distributionby the categoryof TNM system, invasiveness, multifocality, metastases to lymph nodes, type and extent of surgical and radioiodine treatment, and prognosis according to the MACIS criterion. Whether sporadic or familial, the tumor size, metastatic potential, and invasive potential are higher in young people, asalready known. There was no significant difference between the "parents" and "adult" groups of patients in terms of tumor parameters. One exception was the higher frequency of multifocal tumors in the FNMTC patients. Meanwhile, compared to the "young" sporadic papillary carcinomas patients, the FNMTC "children" had a higher frequency of T2 tumors, metastasizing (N1a-N1ab), and multifocal tumors, but a lower frequency of carcinomas with intrathyroidal invasions.In the FNMTC "children" compared to FNMTC "parents" was a higher frequency of T2 tumors, metastasizing carcinomas, and tumors with capsular invasion. FNMTC carcinomas are more aggressive than sporadic ones, especially in patients who are first-degree relatives in a family with parents already diagnosed with the disease.

The high degree of similarity in histopathological and clinical characteristics between radiogenic and sporadic papillary thyroid microcarcinomas in young patients.

The potential overtreatment of patients with papillary thyroid microcarcinoma (MPTC) has been an important clinical problem in endocrine oncology over the past decade. At the same time, current clinical guidelines tend to consider prior radiation exposure as a contraindication to less extensive surgery, even for low-risk thyroid carcinomas, which primarily include microcarcinomas. This study aims to determine whether there are differences in the behavior of MPTC of two etiological forms (radiogenic and sporadic), including invasive properties, clinical data, and recurrence in patients aged up to 30 years. For this purpose, 136 radiogenic (from patients aged up to 18 years at the time of the Chornobyl accident) and 83 sporadic (from patients born after the Chornobyl accident) MPTCs were selected and compared using univariate and multivariate statistical methods in a whole group and in age and tumor size subgroups. No evidence of more aggressive clinical and histopathological behavior of radiogenic MPTCs as compared to sporadic tumors for basic structural, invasive characteristics, treatment options, and postoperative follow-up results was found. Moreover, radiogenic MPTCs were characterized by the lower frequencies of oncocytic changes (OR = 0.392, p = 0.004), nodal disease (OR = 0.509, p = 0.050), and more frequent complete remission (excellent response) after radioiodine therapy (OR = 9.174, p = 0.008). These results strongly suggest that internal irradiation does not affect tumor phenotype, does not associate with more pronounced invasive properties, and does not worsen prognosis in pediatric or young adult patients with MPTC, implying that radiation history may be not a pivotal factor for determining treatment strategy in such patients.

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET–rearranged thyroid cancer.

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys.

Thyroid cancer is the malignant tumor that is increasing most rapidly in the world, mainly at the expense of sporadic papillary thyroid carcinoma. The somatic alterations involved in the pathogenesis of sporadic follicular cell derived tumors are well recognized, while the predisposing alterations implicated in hereditary follicular tumors are less well known. Since the genetic background of syndromic familial non-medullary carcinoma has been well established, here we review the pathogenesis of non-syndromic familial non-medullary carcinoma emphasizing those aspects that may be useful in clinical and pathological diagnosis. Non-syndromic familial non-medullary carcinoma has a complex and heterogeneous genetic basis involving several genes and loci with a monogenic or polygenic inheritance model. Most cases are papillary thyroid carcinoma (classic and follicular variant), usually accompanied by benign thyroid nodules (follicular thyroid adenoma and/or multinodular goiter). The possible diagnostic and prognostic usefulness of the changes in the expression and/or translocation of various proteins secondary to several mutations reported in this setting requires further confirmation. Given that non-syndromic familial non-medullary carcinoma and sporadic non-medullary thyroid carcinoma share the same morphology and somatic mutations, the same targeted therapies could be used at present, if necessary, until more specific targeted treatments become available.

Papillary Thyroid Carcinoma: Current Position in Epidemiology, Genomics, and Classification.

Papillary thyroid carcinoma is the most common type of thyroid malignancy both in adults and pediatric population. Since the 1980s, there are changes in criteria in labelling thyroid lesions as "papillary thyroid carcinomas." Radiation exposure is a well-established risk factor for papillary thyroid carcinoma. Other environmental risk factors include dietary iodine, obesity, hormones, and environmental pollutants. Papillary thyroid carcinomas could occur in familial settings, and 5% of these familial cases have well-studied driver germline mutations. In sporadic papillary thyroid carcinoma, BRAF mutation is common and is associated with clinicopathologic and prognostic markers. The mutation could aid in the clinical diagnosis of papillary thyroid carcinoma. Globally, thyroid cancer is among the top ten commonest cancer in females. In both adult and pediatric populations, there are variations of prevalence of thyroid cancer and rising incidence rates of thyroid cancer worldwide. The increase of thyroid cancer incidence was almost entirely due to the increase of papillary thyroid carcinoma. The reasons behind the increase are complex, multifactorial, and incompletely understood. The most obvious reasons are increased use of diagnostic entities, change in classification of thyroid neoplasms, as well as factors such as obesity, environmental risk factors, and radiation. The prognosis of the patients with papillary thyroid carcinoma is generally good after treatment. Nevertheless, cancer recurrence and comorbidity of second primary cancer may occur, and it is important to have awareness of the clinical, pathological, and molecular parameters of papillary thyroid carcinoma.

Comparison Between Clinicopathological Characteristics, BRAF V600E and TERT Promoter Mutation of Familial Non-Medullary Thyroid Carcinomas, and Sporadic Case.

BackgroundIt has been debated whether familial non-medullary thyroid carcinoma (FNMTC) is more aggressive and has a worse prognosis than sporadic non-medullary thyroid carcinoma (SNMTC). Our aim was to compare the invasiveness and prognosis of FNMTC and SNMTC by their biological behavior and molecular changes.Method and MaterialOur group mainly compared 106 patients with FNMTC whom have complete clinicopathological data during 2011–2019 in West China Hospital, Sichuan University, and 212 randomly selected cases with SNMTC were included to compare their biological behavior, recurrence and mortality, and molecular expression of BRAF V600E and TERT promoter. At the same time, FNMTC cases were divided into four subgroups, namely, two affected members group, three or more affected members, parent/offspring group, and sibling group, and they were compared with SNMTC separately to analyze the difference in their invasiveness and prognosis.ResultsWe found that the mean tumor size of FNMTC (0.96 ± 0.53cm) was smaller than that of SNMTC (1.15 ± 0.72 cm) (p = 0.020), while no significant difference in the incidence of other clinicopathological factors, including bilateral growth, capsular invasion, with thyroid nodular goiter or not, multifocality, lymph node metastasis, extrathyroidal extension, iodine 131 treatments, T stage, and American Joint Committee on Cancer (AJCC) stage, was observed between FNMTC and SNMTC (p > 0.05), between each FNMTC subgroup (p > 0.05), and between each FNMTC subgroup and SNMTC (p > 0.05). There was no significant difference in recurrence, mortality, and BRAF V600E and TERT promoter mutation between FNMTC and SNMTC, among which 50/60 (83.33%) of FNMTC patients had BRAF V600E mutation and 1/32 (3.13%) had TERT promoter mutation, while the mutation rates of SNMTC were 93/108 (86.11%) and 3/64 (4.69%) (p > 0.05).ConclusionThere was no significant difference in invasiveness and prognosis between FNMTC and SNMTC by biological behavior, patient survival, and molecular level comparison.

The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age

Simple SummaryAnalysis of the groups of young Ukrainian patients (aged ≤28 years) with radiogenic and sporadic papillary thyroid carcinomas (PTCs) showed that the frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences, while the BRAFV600E-negative tumors differed markedly and displayed a higher frequency of invasive tumor features in the radiogenic PTCs. Hence, there is evidence that BRAFV600E does not confer a more aggressive course of PTC in young patients regardless of tumor etiology.Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study

Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.

ABSTRACTCancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The TgCreERT2;BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.

Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features.

DICER1 germline mutations cause DICER1 syndrome, in which multinodular goitre is a common feature. Recently, somatic DICER1 mutations have been reported in sporadic thyroid carcinomas, of which the newly described macrofollicular variant of follicular thyroid carcinoma (MV-FTC) seems particularly enriched for this aberrancy. We report here histological and genetic findings in five follicular thyroid tumours with macrofollicular architecture (four carcinomas and one adenoma). We have diagnosed five cases during a year-long period at the Karolinska University Hospital, a tertiary thyroid cancer center with a catchment area of approximately 2.3 million inhabitants. Tumour DNA was interrogated using a commercially available massive parallel sequencing platform. All cases were female patients, ranging from 13 to 33years at surgery. A single patient was a DICER1 syndrome carrier; the others were sporadic cases. All tumours displayed a macrofollicular architecture with a broad capsule. The MV-FTCs displayed capsular invasion, but never vascular invasion. Areas with degenerative changes (microinfarctions) were noted in all cases, and focal papillary growth was observed in the majority. The Ki-67 proliferation index was always above 4%. All cases displayed DICER1 gene mutations, of which four of five cases displayed RNase IIIb hot-spot missense mutations adjoined by a second, deleterious variant in three of five tumouurs. Macrofollicular variants of follicular thyroid tumours are predominantly found in younger females and are strongly linked to somatic DICER1 gene mutations. Histological features such as a broad tumorous capsule, focal infarctions and areas with papillae could constitute clues prompting further genetic analyses.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus.

Simple SummaryChildhood papillary thyroid carcinomas (PTCs) detected after the Chernobyl accident were genetically characterized by a high prevalence of gene rearrangements and low frequency of point mutations. However, no reports on genetic alterations in sporadic childhood PTCs from the Chernobyl-affected regions are available. This study investigated a series of PTCs from children of Belarus not exposed to radiation, and found that fusion genes were significantly more prevalent than point mutations in these tumors. Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and the reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC largely parallels that in Chernobyl PTC, although the distribution of oncogene types suggests less aggressive clinical presentation of sporadic PTC, especially than that of early-onset radiation-related PTC.Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

Abstract 2035: Alterations in nuclear DNA organization in sporadic pediatric Papillary Thyroid Carcinoma (PTC)

Abstract Pediatric papillary thyroid carcinoma (PTC) present a more aggressive disease than adults, with higher risk of malignancy, higher rates of metastasis, multifocality and larger tumor sizes. We described AGK-BRAF fusion in 19% of sporadic pediatric PTC, which is associated with lung metastasis and younger age (mean 10.67 y.o.). Super-resolved three-dimensional structured illumination microscopy (3D-SIM) allows the visualization of the DNA structure inside the interphase nucleus at microscopic length scales. 3D-SIM has shown that cancer cell nuclei exhibit chromatin remodeling, with increased amount of DNA-poor spaces, which indicates a disrupted pattern in the DNA and has been associated with aggressive behavior in other tumor subtypes. In order to understand the underlying causes of the aggressiveness of pediatric PTC, we here aimed to analyze, for the first time, the DNA organization from 13 pediatric PTC patients (≤18 y.o.), using super-resolved 3D-SIM technology. A granulometry-based measurement method quantified the size distribution of DNA structure (DNA packaging) and DNA-poor spaces. We compared the granulometry for: tumor vs normal tissues; AGK-BRAF fusion (positive vs negative tumors); distant metastasis (presence vs absence); multifocal vs unifocal tumors; age at diagnosis (≤ 10 y.o. vs > 10 y.o.); tumor size ( ≤ 2 cm vs > 2 cm) and extra-thyroidal (ET) extension (presence vs absence). Nuclei from tumor cells exhibited larger DNA structures (p=0.0001) and more DNA-poor spaces (p<0.0001) than normal cells. In relation to the clinicopathological features, patients that presented distant metastasis (p=0.001), multifocal tumors (p=0.002) and > 2 cm tumors (p=0.0029), exhibited more DNA-poor spaces in their nuclei. Regarding the analyses of the AGK-BRAF fusion, borderline results were observed for both DNA structure (p=0.058) and DNA-poor spaces (p=0.053). Similar results were observed in PTC cases with age ≤10 y.o. for DNA structure (p=0.068) and DNA-poor spaces (p=0.06). No significant difference was observed for ET extension. Our preliminary data corroborate with previous studies, where tumor cell nuclei present more DNA-poor spaces than normal cells; and suggest a progressive disruption and remodeling of the chromatin in malignant cells. Interestingly, tumor cells from patients with features of poor prognosis (distant metastasis, multifocality and tumor size) can exhibit a more disrupted DNA organization, which can be related to a more aggressive behavior of the tumor. Moreover, can also observe a trend to a more disrupted chromatin organization in AGK-BRAF tumors and tumors from <10 y.o. patients, which can be associated with the aggressiveness of the disease in these cases. Further analysis are needed to better understand wether AGK-BRAF fusion is associated with poor prognosis in pediatric PTC and if it could be related to a high genomic instability caused by this fusion. Citation Format: Luiza Sisdelli, Maria I. Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Aline Rangel-Pozzo, Sabine Mai, Janete M. Cerutti. Alterations in nuclear DNA organization in sporadic pediatric Papillary Thyroid Carcinoma (PTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2035.

RETROSPECTIVE COHORT STUDY: DIFFERENCES AND SIMILARITIES BETWEEN SPORADIC AND FAMILIAL PAPILLARY THYROID CARCINOMA

Abstract INTRODUCTION There is a lot of controversy around the study of the familial papillary thyroid carcinoma (CPFT), which has a different behaviour than sporadic. The aim of this investigation is to establish the differences and similarities between sporadic papillary thyroid carcinoma and the familial one in order to determine if the familial type is a more aggressive clinical entity than sporadic. MATERIAL AND METHODS A retrospective cohort study in 231 patients with papillary thyroid carcinoma (CPT) from 2006 to 2018. One group was established according to the presence of two or more relatives as CPFT (n = 46) and the other group were the sporadic cases (n = 185). Throughout this study the clinical-pathological characteristics of both groups were compared based on the analysis of twenty-one variables. RESULTS After having carried out this investigation, statistically significant differences have only been found in the vascular invasion (p < 0.001), presenting 3.8% in the sporadic group compared to the 21.7% found in the CPFT with an Odds Ratio of 7.6. CONCLUSIONS Based on our experience, patients with CPFT present a higher frequency of multifocal neoplasia, capsular invasion, vascular invasion, lymph node invasion and recurrence than sporadic CPT. However, these differences were only significant while analyzing the vascular invasion variable. Although the results of our study have been unable to prove that the CPFT is more aggressive than sporadic CPT, we recommend performing periodic ultrasounds such as the screening of the members of the families with CPFT. Finally, we conclude that more studies are needed.

Longer Time to Reach Excellent Response to Treatment in Familial Versus Sporadic Non-medullary Thyroid Cancer (NMTC): A Matched Case-Control Study.

BackgroundFamilial non-medullary thyroid cancer (NMTC) are supposed to be more aggressive and require more frequent treatment compared to non-familial thyroid cancer.ObjectivesThis matched case-control study aimed to compare the response to treatment between the matched case-control groups of familial and sporadic NMTC.MethodsThis is a retrospective study in patients with familial NMTC (at least one other first-degree relative involved) who were treated with surgery, followed by radio-iodine therapy (RIT) without consideration of its familial origin. Response to treatment was compared between familial NMTC and age, sex, and TNM stage-matched non-familial NMTC (control group). Response to treatment was assessed one and two years after RIT, and time to excellent response was identified.ResultsOut of 2,944 NMTC patients, 81 (2.75%) patients had familial NMTC. We compared 66 patients with familial NMTC and 66 sporadic NMTC patients. There was no significant difference in first thyroglobulin, initial and accumulative iodine dose, and additional treatments (additional surgery and radiotherapy) between patients and controls. Although no significant difference was noted in one and two years’ responses to treatment between the case and control groups, familial NMTC patients required more time to achieve excellent response (26.7 ± 24.9 versus 15.9 ± 9.0 months, P = 0.01). No significant difference was noted between familial NMTC patients with two or more than two involved relatives.ConclusionsOur study showed that if patients with familial NMTCs were treated in the same way as non-familial patients, the time to excellent response would be significantly longer, even when they have only one other involved relative.