Sporadic Papillary Thyroid Carcinoma Research Articles

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.

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.

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.

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.

Molecular pathogenesis of pediatric thyroid carcinoma.

ABSTRACTThere has been little understanding of the molecular pathogenesis of pediatric thyroid cancers. Most of them are histologically classified as papillary thyroid carcinoma (PTC). Ionizing radiation is the most important environmental factor to induce PTC, especially in children. Particularly, radiation-related pediatric PTCs after the Chernobyl accident provided invaluable information. In addition, the recent accumulation of sporadic pediatric PTC cases, partly due to advances in diagnostic imaging, has also provided insight into their general pathogenesis. In PTC development, basically two types of genetic alterations, fusion oncogenes, mainly RET/PTC, and a point mutation, mainly BRAFV600E, are thought to play a key role as driver oncogenes. Their frequencies vary depending on patient age. The younger the age, the more prevalent the fusion oncogenes are. Higher incidence of fusion oncogenes was also observed in cases exposed to radiation. In short, fusion oncogenes are associated with both age and radiation and are not evidence of radiation exposure. The type of driver oncogene is shifted toward BRAFV600E during adolescence in sporadic PTCs. However, until about this age, fusion oncogenes seem to still confer dominant growth advantages, which may lead to the higher discovery rate of the fusion oncogenes. It has been postulated that RET/PTC in radiation-induced PTC is generated by ionizing radiation; however, there is an interesting hypothesis that thyroid follicular cell clones with pre-existing RET/PTC were already present, and radiation may play a role as a promoter/progressor but not initiator. Telomerase reverse transcriptase gene (TERT) promoter mutations, which are the strongest marker of tumor aggressiveness in adult PTC cases, have not been detected in pediatric cases; however, TERT expression without the mutations may play a role in tumor aggressiveness. In this paper, the recent information regarding molecular findings in sporadic and radiation-associated pediatric PTCs is summarized.

Abstract 3553: Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC)

Abstract The incidence of thyroid carcinoma has increased worldwide, including in pediatric patients. Papillary thyroid carcinoma (PTC) is the most common subtype. Previous studies have suggested that clinical presentation and outcome diverge between pediatric and adult PTC and that this difference is likely due to distinct genetic alterations. BRAF V600E point mutation is highly prevalent in adults, while genetic fusions (RET/PTC, AGK-BRAF, ETV6-NTRK3) are the most prevalent events in the pediatric population. As telomere loss or dysfunction results in aneuploidy and chromosomal rearrangements, which can promote carcinogenesis, we investigated the three-dimensional (3D) structure of the telomeres in the nuclei from 21 pediatric patients (≤18 y.o), representing 16 PTC cases (with paired normal and tumor tissues for five of them) and five normal thyroid tissues from patients undergoing thyroidectomy for reasons other than cancer. We performed quantitative fluorescence in situ hybridization (FISH), 3D imaging, and 3D telomere analysis using TeloView® software to examine telomere dysfunction. The parameters examined included total number of signals (numbers of telomeres), total number of telomere aggregates, a/c ratio (indicating the phase of the cell cycle), total intensity (telomere length) and nuclear volume. Thyroid cancer cells showed lower average intensity of signals (p<0.0001) and lower intensity signals (p<0.0001), as well as higher nuclear volume (p<0.0001), compared to normal thyroid cells. In addition, tumour cells showed a higher a/c ratio (p<0.0001), indicating that they are more actively dividing than normal cells, which correlates with the high proliferation rate of cancer cells. We did not observe any alterations related to the total number of telomere signals and total number of aggregates, which suggests no significant aneuploidies occurring with these samples. The 3D nuclear telomere signature was able to detect differences in telomere architecture in tumours, compared to normal. Further analysis is necessary to define whether nuclear telomere architecture and specific genetic alterations observed in pediatric thyroid cancer are associated. Citation Format: Luiza Sisdelli, Maria Isabel Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Monique O. Freitas, Aline Rangel-Pozzo, Sabine Mai, Janete Cerutti. Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3553.

Long-Term Clinical Outcome in Familial and Sporadic Papillary Thyroid Carcinoma

Background: The definition and the behaviour of familial papillary thyroid cancer (FPTC) compared to the sporadic form (SPTC) are still debated. Some authors believe that only families with 3 or more affected members represent an actual example of familial diseases. Objectives: The objective of the study was to analyse the clinicopathological features and the outcome of sporadic and familial PTC patients also according to the number of affected members. Methods: Among 731 patients, we identified 101 (13.8%) with familial diseases, 79 with 2 affected members (FPTC-2) and 22 with 3 or more affected members (FPTC-3) followed for a mean period of 10 years. Results: FPTC patients had more frequently bilateral tumour (p = 0.007). No difference was found between the 2 groups for the other evaluated variables. At the time of the first follow-up (1–2 years after initial therapy), FPTC patients had a higher rate of persistent disease. However, at the last follow-up, the clinical outcome was not different between sporadic and familial patients. When the comparison between SPTC and FPTC was performed, according to the number of affected members, a significant trend between the 3 groups was observed for tumour diameter (p = 0.002) and bilaterality (p = 0.003), while we did not observe a significant trend for both response to initial therapy (p = 0.15) and last clinical outcome (p = 0.22). Conclusions: Our results suggest that, although the clinicopathological features of FPTC may be more aggressive, the long-term outcome is similar between FPTC and SPTC. A possible explanation is that PTC has a favourable prognosis, even when clinical presentation is more aggressive.

The clinicopathologic characteristics of familial and sporadic papillary thyroid carcinoma in Turkish patients

Background/aim The aim of this study is to investigate clinicopathologic features of familial papillary thyroid carcinoma (fPTC) and compare them with sporadic papillary thyroid carcinoma (sPTC) in Turkish patients. A retrospective analysis of the papillary thyroid carcinoma (PTC) cases, with or without family history with a follow-up around 10 years was performed. Materials and methodsA series of patients with fPTC (82 fPTC families with 146 affected individuals) were compared with patients with sPTC (n = 112). The clinicopathologic features [(age, gender, histologic subtype, tumour size, bilaterality, multifocality, extrathyroidal extension (ETE), lymph node metastasis (LNM)] and treatment procedures (lymph node dissection, radioactive iodine ablation), and the outcomes like recurrences in the neck region, distant metastasis, and the need for reoperation were compared between the groups.Results When the groups were compared, there was no significant difference in age (P = 0.449), and tumour size (P = 0.898) between familial and sporadic PTC patients. fPTC group had a significantly higher risk of male gender (P=0.001), bilaterality (P = 0.004), multifocality (P = 0.011), LNM (P = 0.013), ETE (P = 0.040), and distant metastasis (P ≤ 0.0001) than the sPTC group. However, recurrence rate was similar between the 2 groups (P = 0.436).Conclusion The results of this study confirms a more aggressive nature in fPTC patients, in terms of bilaterality, multifocality, ETE, LNM, and distant metastasis, compared to sPTC patients in Turkish population.

Chromosomal Rearrangements of RET/PTC in Post-Chernobyl Thyroid Cancer

A hypothesis is proposed here that RET rearrangements in papillary thyroid cancers are related to the disease duration and tumor progression. The most common RET rearrangements are RET/PTC1 and RET/PTC3. RET/PTC1 is more prevalent in classic papillary thyroid carcinoma (PTC), its diffuse sclerosing variant, and papillary microcarcinoma; while RET/PTC3 is frequently found in less differentiated solid PTC. RET/PTC3 is associated with larger tumor size and multifocality in sporadic pediatric PTC. The RET rearrangements; especially RET/PTC3, which is frequently detected among Chernobyl thyroid cancers is developed after exposure to radiation at an early age, is proposed to be a potential trigger of malignancy. There are many late-stage tumors among the first-wave Chernobyl PTCs that tend to be larger and less differentiated than those detected later. The high proportion of late-stage cases shortly after the accident is explained by the neglected cases in the screening process and also by the fact that some non-exposed patients were registered as radiation-exposed. The screening was productive because of the reservoir of undiagnosed cases in the population: registered incidence of thyroid cancer (TC) among children and adolescents prior to the Chernobyl disaster was low in the Soviet Union; compared to other developed countries. In conclusion, RET rearrangements, especially RET/PTC3, were correlated with the tumor progression. If the hypothesis defended here is correct, a low prevalence of RET/PTC3 among sporadic TC is circumstantial evidence of efficient cancer diagnosis and early detection.

Histopathological characteristics and post-operative follow-up of patients with potentially radiogenic papillary thyroid carcinoma depending on oncocytic changes availability in the tumor cells.

To compare the frequency of main histopathological characteristics, 131І thyroid radiation doses, invasive properties and post-operative follow-up of patients of different age groups with potentially radiogenic papillary thyroid carcinoma (PTC) with the presence and absence of oncocytic changes in tumor cells. PTC removed in 483patients from high risk age-group for radiogenic thyroid cancer development (children and adolescents at the time of Chornobyl accident who lived in the northern regions of Ukraine: Kyiv, Zhytomyr, and Chernihiv regions) have been studied microscopically. The frequency of PTC with the presence of oncocytic changes (OCh) in tumor cells increased significantly with increasing of patients' age at the time of surgery: from 8.3% in children 4-14years old to 54.3% in adults 39-48years old (ptrend < 0.0001). The presence of such changes is associated with papillary and solid-trabecular dominant tumor growth pattern in more than 90% of cases in each age group. The mean 131І thyroid dose in the whole series of PTC patients with OCh was significantly lower compared to the same index in PTC patients without OCh (493.7mGy and 765.8mGy, respectively, p < 0.0001). In addition, regional metastases recurrences were revealed more frequently in patients with OCh in primary PTC compared with patients without OCh in primary tumor (7.2% vs 1.5%, p = 0.0022). Significantly increasing age-trend of OCh in PTC of patients affected by the Chornobyl fallout and operated at age from 4to 48years, as well as opposite decreasing linear age-trend of 131І thyroid dose may reflect a gradual increase of sporadic PTCs frequency in the potentially radiogenic series with time elapsed since accident. The frequency of oncocytic insensitive to radioiodine therapy of lymph node metastases recurrences also increased with patients age and OCh availability in primary PTC.

SNP Association with Risk for Sporadic Papillary Thyroid Carcinoma in Kazakh Population

Background: The recent genome-wide association studies (GWAS) including FOXE1 and NKX2-1 genes have represent associations for well differentiated thyroid carcinoma. Replication studies in geographically distinct populations identified strong associations of rs965513 (9q22.33) and rs944289 (14q13.3) SNPs with papillary thyroid cancer. This work is the first to characterise the associations of SNPs in a population-based Kazakh cohort.Aims: To study association of SNPs with risk for sporadic papillary thyroid carcinoma (PTC) in Kazakh population.Materials and methods: A total of 298 patients with histologically confirmed PTC and 742 controls of Kazakh origin were recruited. All participants donated a peripheral venous blood sample which was used to isolate genomic DNA. Genotyping was performed using TaqMan Genotyping on a Light Cycler 480 (Roche, Indianapolis, IN).Results: Significant associations: rs965513 (p=3.24 E-16; OR=2.05, 95% CI 1.82−2.11) and rs944289 (p=1.38 E-06; OR=1.39, 95% CI 1.21−1.52) were found in the multiplicative model of inheritance adjusted for age and sex.Conclusions: Our study unambiguously confirms the existence of genetic determinants of susceptibility to PTC in Kazakh population.

Comparative Histopathologic Analysis of "Radiogenic" and "Sporadic" Papillary Thyroid Carcinoma: Patients Born Before and After the Chernobyl Accident.

The issue of whether radiation-induced thyroid cancer is pathologically different from sporadic remains not fully answered. This study compared structural characteristics and invasive features of papillary thyroid carcinoma (PTC) in two age-matched groups: patients who were children (≤4 years old) at the time of the Chernobyl accident and who lived in three regions of Ukraine most contaminated by radioactive iodine 131I ("radiogenic" cancer), and those who lived in the same regions but who were born after 1987 and were not exposed to 131I ("sporadic" cancer). Further, the histopathologic features of PTC were analyzed in relation to age and individual 131I thyroid dose. The study included 301 radiogenic and 194 sporadic PTCs. According to age at surgery, patients were subdivided into children (≤14 years old), adolescents (15-18 years old), and adults (19-28 years old). Statistical analyses included univariate tests and multivariable logistic regression within and across the age subgroups. Analyses of morphological features related to 131I doses were conducted among exposed patients on categorical and continuous scales controlling for sex and age. Among children, radiogenic PTC displayed a significantly higher frequency of tumors with a dominant solid growth pattern, intrathyroidal spread, extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adolescents more frequently displayed extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adults more frequently had intrathyroidal spread and extrathyroidal extension. The frequency of PTC with dominant papillary pattern and oxyphilic cell metaplasia was significantly lower in radiogenic compared to sporadic tumors for all age groups. Manifestations of tumor aggressiveness were most frequent in children compared to adolescents and adults regardless of etiology. Radiogenic PTC is less likely to demonstrate a dominant papillary growth pattern and more likely to display more aggressive tumor behavior than sporadic PTC. Histopathologic tumor aggressiveness declines with patient age in both radiogenic and sporadic cases.

Abstract 2082: NMS-E668, a potent and selective RET kinase inhibitor characterized by specificity towards VEGFR2 and high antitumor efficacy against RET-driven models

Abstract RET, a receptor tyrosine kinase (RTK) expressed mainly in neural crest-derived tissues, plays a role in cell growth and differentiation and its physiological activation depends upon binding to the GDNF family. Genetic aberrations leading to constitutive RET activation are well-established as oncogenic events. Activating point mutations of RET, for example, are present in ca. 70% of medullary thyroid carcinoma patients including all hereditary cases, while RET gene rearrangements resulting in production of activated RET fusion proteins occur in approximately 10% of sporadic papillary thyroid carcinomas. More recently, recurring RET gene rearrangements have also been found in 1-2 % of lung adenocarcinomas and subsets of other solid tumors including colorectal and salivary gland carcinomas. Thus RET kinase represents an actionable therapeutic target in multiple clinical settings with high medical need. Consequently several small-molecule inhibitors targeting this kinase have been explored in clinical settings. A common feature of most advanced agents is their lack of selectivity and in particular their potent cross-reactivity against VEGFR2, an RTK whose inhibition is associated with serious, dose-limiting cardiovascular toxicity. Indeed, the high homology between the two kinases renders identification of ATP competitive compounds that selectively inhibit RET over VEGFR2 a highly challenging task. Here we describe the preclinical activity of NMS-E668, a potent and selective ATP-competitive RET inhibitor characterized by favorable activity, selectivity and ADME profiles. Biochemically, NMS-E668 has an excellent selectivity profile against a panel of &amp;gt;50 kinases, notably including &amp;gt;10-fold selectivity over VEGFR2. Selectivity of NMS-E668 for RET vs. VEGFR2 was confirmed in NIH-3T3 cells engineered to express activated forms of these kinases. NMS-E668 potently (IC50 circa 50 nM) and selectively inhibited proliferation of RET-dependent tumor cells, including TT medullary carcinoma cells harboring a RET C634W activating point mutation and LC2/ad lung carcinoma cells bearing the oncogenic fusion protein CCDC6-RET. NMS-E668 also potently inhibited IL3-independent growth of Ba/F3 cells expressing KIF5B-RET, the RET rearrangement that is most commonly found in lung adenocarcinomas. Cellular mechanism studies confirmed that NMS-E668 inhibits RET autophosphorylation and downstream signaling at doses consistent with antiproliferative activity. Tested in vivo against KIF5B-RET-driven Ba/F3 tumors, NMS-E668 displayed &amp;gt;90% tumor growth inhibition accompanied by target modulation following oral administration at 10 and 20 mg/kg, with prolonged tumor regressions observed at the higher dose. Thus NMS-E668, a potent and VEGFR2-sparing RET inhibitor is an innovative and highly promising candidate for further development. Citation Format: Elena Ardini, Patrizia Banfi, Nilla Avanzi, Marina Ciomei, Paolo Polucci, Alessandra Cirla, Antonella Ermoli, Ilaria Motto, Elena Casale, Giulia Canevari, Cinzia Cristiani, Sonia Troiani, Federico Riccardi Sirtori, Nadia Amboldi, Dario Ballinari, Francesco Caprera, Eduard Felder, Arturo Galvani, Daniele Donati, Antonella Isacchi, Maria Menichincheri. NMS-E668, a potent and selective RET kinase inhibitor characterized by specificity towards VEGFR2 and high antitumor efficacy against RET-driven models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2017-2082

The p.G534E variant of HABP2 is not associated with sporadic papillary thyroid carcinoma in a Polish population.

Thyroid cancer is one of the most frequently diagnosed cancers of the endocrine system. There are no known genetic risk factors for non-medullary thyroid cancer, other than a small number of hereditary syndromes; however, approximately 5% of non-medullary thyroid cancer, designated familial non-medullary thyroid cancer, exhibits heritability. The p.G534E (c.1601G>A) variant of HABP2 was recently reported as a risk factor for familial non-medullary thyroid cancer, including papillary thyroid carcinoma. We analyzed the incidence of the c.1601G>A variant of HABP2 in a Polish population consisting of 326 cases of papillary thyroid carcinoma and 400 control individuals by DNA genotyping, performed by Sanger sequencing. The c.1601G>A variant was detected in 3.7% of sporadic papillary thyroid carcinoma cases and 4.7% of healthy controls, and we did not detect an association between this variant and sporadic papillary thyroid carcinoma risk (OR = 0.71, 95% CI: 0.33–1.51; p = 0.3758). Additionally, no significant associations were identified between clinical and pathological disease features, response to primary treatment, and clinical status at the end of the observation, and HABP2 c.1601G>A genotype. In conclusion, the p.G534E variant of HABP2 is not associated with sporadic papillary thyroid carcinoma risk in the Polish population.

HABP2 p.G534E variant in patients with family history of thyroid and breast cancer.

Familial Papillary Thyroid Carcinoma (PTC) has been described as a hereditary predisposition cancer syndrome associated with mutations in candidate genes including HABP2. Two of 20 probands from families with history of PTC and breast carcinoma (BC) were evaluated by whole exome sequencing (WES) revealing HABP2 p.G534E. Sanger sequencing was used to confirm the involvement of this variant in three families (F1: 7 relatives; F2: 3 and F3: 3). The proband and his sister (with no malignant tumor so far) from F1 were homozygous for the variant whereas one relative with PTC from F2 was negative for the variant. Although the proband of the F3 with PTC was HABP2 wild type, three relatives presented the variant. Five of 170 healthy Brazilian individuals with no family history of BC or PTC and three of 50 sporadic PTC presented the p.G534E. These findings suggested no association of this variant with our familial PTC cases. Genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2) were detected by WES, suggesting that other cancer-associated genes have pathogenic effects in the risk of familial PTC development.

Comparative histopathological analysis of sporadic pediatric papillary thyroid carcinoma from Japan and Ukraine.

This study set out to compare structural and invasive characteristics of sporadic papillary thyroid carcinoma (PTC) in age-matched groups of children and adolescents of Japan and Ukraine to provide detailed histopathological analysis of tumors from different geographical areas with different iodine intake. A total of 348 (160 Japanese and 188 Ukrainian) PTCs from patients without radiation history were analyzed initially as a combined pediatric group and then subdivided into childhood (aged ≤14 years) and adolescent (aged from 15 to ≤18 years) age series. On multivariate comparison, the Japanese pediatric PTC was characterized by a higher sex ratio (p=1.504E-4), and a higher frequency of microcarcinoma (p=0.039), papillary dominant growth pattern (p=0.024), focal oxyphilic cell metaplasia (p=7.644E-6), intrathyroid spread (p=0.010), lymphatic/vascular invasion (p=0.01) and regional lymph node metastases (p=3.540E-6). In the Ukrainian group, multifocal (p=0.004) and non-encapsulated tumors with the solid-trabecular growth pattern (p=0.05) were more frequent. Childhood Japanese PTCs differed from Ukrainian PTCs by more pronounced invasive properties such as lymphatic/vascular invasion and nodal disease, but did not differ by the dominant growth pattern. In adolescents, the differences were detected not only for lymph node metastases, but also for a higher frequency of the papillary dominant pattern in Japanese PTC. Overall, significantly higher frequencies of oxyphilic cell metaplasia and more pronounced invasive features observed in the Japanese PTC in both age-matched series represent the major differences between the tumors from two geographical areas.

Fusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children.

Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients. Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAFV600E and NRASQ61) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data. Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAFV600E in 3 (9%). No mutation was found in NRASQ61. BRAFV600E was associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05). The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.