Sporadic Thyroid Cancer Research Articles

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

Patients with PTEN hamartoma tumor syndrome (PHTS), a molecular diagnosis for those carrying germline PTEN pathogenic variants, have a high prevalence of benign and malignant thyroid disease. Characterizing the genomic landscape in PHTS thyroid tumors could provide insights into malignant potential and tumor progression to help optimize diagnosis, surveillance, and treatment in this population. To reveal the somatic alterations in PHTS-associated thyroid tumors, we conducted exome sequencing on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS. A control cohort of 447 sporadic papillary thyroid cancers (PTC) from The Cancer Genome Atlas was used for comparison. PHTS-associated thyroid tumors had a unique genomic landscape in the setting of a pathogenic germline PTEN mutation, when compared with the general population. PHTS-associated thyroid tumors demonstrated a high frequency of second-hit somatic PTEN alterations, including variants and loss-of-heterozygosity events. Second-hit somatic PTEN alterations were more prevalent in PHTS-associated PTC than sporadic PTC (65.2% vs. 0.067%), occurring frequently in PHTS-associated follicular thyroid cancer (100%) and benign follicular nodules (90%). PHTS-associated PTC additionally harbored somatic alterations in BRAF, RAS family members, and genes associated with DNA double-stranded break repair, as well as somatic arm-level copy-number variations. Together, these findings suggest that biallelic PTEN alterations may function as foundational mutations in PHTS thyroid tissue, promoting benign growth and increasing potential for malignant transformation through impaired DNA double-stranded break repair and increased genomic instability. The unique genomic landscape of PHTS-associated thyroid tumors carries implications for molecular-targeted therapies for patients. Significance: 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.

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.

Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers.

Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10-20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET mutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selective RET inhibitors, selpercatinib and pralsetinib, have revolutionized the field of RET precision therapy. In this article, we review the current status on the use of the selective RET inhibitor, selpercatinib, in RET fusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.

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.

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.

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.

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.

Familial non-medullary thyroid carcinoma: clinico-pathological features, current knowledge and novelty regarding genetic risk factors.

Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers and occurs in two or more first-degree relatives in the absence of predisposing environmental factors. Out of all FNMTC cases, only 5% are represented by syndromic forms (Gardner's Syndrome, familial adenomatous polyposis, Cowden's Syndrome, Carney complex 1, Werner's Syndrome and DICER1 syndrome), in which thyroid cancer occurs as a minor component and the genetic alterations are well-known. The non-syndromic forms represent the majority of all FNMTCs (95%), and the thyroid cancer is the predominant feature. Several low penetration susceptibility risk loci or genes (i.e. TTF1, FOXE1, SRGAP1, SRRM2, HABP2, MAP2K5, and DUOX2), here fully reviewed, have been proposed in recent years with a possible causative role, though the results are still not conclusive or reliable. FNMTC is indistinguishable from sporadic non-medullary thyroid cancer (sNMTC), which means that FNMTC cannot be diagnosed until at least one of the patient's first-degree relatives is affected by tumor. Some studies reported that the non-syndromic FNMTC is more aggressive than the sNMTC, being characterized by a younger age of onset and a higher rate of multifocal and bilateral tumors, extrathyroidal extension, lymph node metastasis, and recurrence. On the contrary, other studies did not find clinical differences between non-syndromic FNMTCs and sporadic cases. Here, I reported an extensive review on genetic and clinico-pathological features of the FNMTC, with particular attention on novel genetic risk factors for non-syndromic forms.

Abstract 2073: Exome sequencing reveals PTPRS, NOTCH3, FGFR1/3 mutations as novel mutational features in medullary thyroid cancer

Abstract Background: Approximately 1,000 patients are diagnosed with medullary thyroid cancer (MTC) in the United States each year; a tumor type that disproportionately causes thyroid cancer-related death. The molecular hallmark of MTC are mutations of the Rearranged During Transfection (RET) proto-oncogene: ~25% of MTC patients harbor germline RET variants and somatic RET mutations can be found in ~ 40% of sporadic medullary thyroid cancers. However, with the exception of RAS mutations relatively little is known of the broad molecular landscape of MTC. Material &amp; Methods: To further explore the mutational features of MTC, we performed whole exome sequencing on paired tumor and normal tissue on a cohort of 14 patients with MTC. For variant calling, we focused on the 468 genes included in the MSK-IMPACT panel. Paired RNA sequencing was available for 7 patients. A variant was included as potential pathogenic based on a combination of SIFT, Polyphen and clinical significance prediction. Only coding variants were considered. Results: Out of the 14 patients, 43% were female (n=6), and 57% (n=8) were male (Table 1). The median age was 55.5 years (range: 21-79 years). At time of diagnosis, 29% had stage I (n=4), 14% stage II (n=2), 21% stage III (n=3), and 36% (n=5) had stage IV disease. The majority of patients (71%, n=10) had multifocal disease. While half of the patients had lymphovascular tumor invasion (50%, n=7), only 14% (n=2) had capsular invasion. Of all patients, 29% (n=4) of patients were germline RET mutation carriers. In our somatic tumor profiling, we detected a total of 23 potential pathogenic variants. The median mutation burden per patient was 2 (range= 0-7). Three patients had no detectable mutations. Expectedly, mutations in the RET gene were also the most frequent somatic mutational events and were detected in 43% (n=6) patients. Interestingly, we identified recurrent mutations in 3 genes that to the best of our knowledge have not been previously described in MTC. Protein- Tyrosine phosphate receptor-type sigma (PTPRS), Notch receptor 3 (NOTCH3), and Fibroblast growth factor receptors1/3 (FGFR1/3). Each of these was mutated in 21% (n=2) MTC patients. In addition, 10 genes were found mutated in a single MTC patient (CHEK2, DNMT1, EP300, GNAS, KMT2A, PIK3C2G, PNRC1, POLE, PRKAR1A, SOX2). In the RET wildtype patients, DNMT1, FGFR1, KMT2A, PIK3C2G, PRKAR1A and PTPRS were the only detected lesions, suggesting a possible pathophysiological importance independent of RET. Conclusions: Our exome sequencing study identified recurrent mutations in PTPRS, NOTCH3, FGFR1/3 as novel recurrent mutational features in MTC. Notably, some of them were detected in RET wildtype patients, suggesting a possible functional role of the genes in carcinogenesis. The functional studies to further define the roles of these gene mutations in MTC are ongoing. Citation Format: Isaiah Boateng, Ayse S. Yilmaz, Pamela Brock, Sandya Liyanarachchi, Ravi Patel, Christopher J. Walker, John Phay, Albert de la Chapelle, Matthew Ringel, Ann-Kathrin Eisfeld. Exome sequencing reveals PTPRS, NOTCH3, FGFR1/3 mutations as novel mutational features in medullary thyroid cancer [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 2073.

Is Familial Nonmedullary Thyroid Cancer A More Aggressive Type of Thyroid Cancer?

Familial non-medullary thyroid cancer (FNMTC) is a distinct entity, increasingly diagnosed. By lacking an accurate genetic diagnostic test, its diagnosis is currently clinically based, with an ongoing debate over whether it has a more aggressive clinical behavior than sporadic non-medullary thyroid cancer (SNMTC). We seek to compare in this study, the clinicopathological variables, and the outcome of FNMTC versus SNMTC patients. We retrospectively searched a database of 465 patients that underwent thyroidectomy at Assaf Harofeh Medical Center (91.4% between 1990 and 2019) for demographics, risk factors, medical history, diagnostic workup, primary treatment, follow-up, and disease outcome data. We compared 47 FNMTC versus 321 SNMTC patients, and FNMTC patients with ≥2 (n = 34) versus ≥3 (n = 13) first-relative affected members. There were no significant differences in demographics, histopathology, TNM stage, treatment, and disease outcome between the FNMTC and SNMTC groups. The T2 and T4 tumor stage in the ≥3-member group were 25% and 8.3% compared to 0% and 0% in the two-member group (P = .02 and P = ns, respectively). Also, LN involvement was significantly higher in the ≥3-member group (61.6% vs. 24.2%, respectively; P = .036). FNMTC is not a more aggressive disease than SNMTC, but this may not apply for the ≥3-affected-relatives group. A large multicenter study including only families with three or more affected relatives is needed. Until then, a family history of NMTC should not be overlooked. 3/5 Laryngoscope, 131:E677-E681, 2021.

Should Total Thyroidectomy Be Recommended for Patients with Familial Non-medullary Thyroid Cancer?

It is unknown whether familial non-medullary thyroid cancer (FNMTC) has more aggressive clinical features and a worse prognosis than sporadic non-medullary thyroid cancer (SNMTC). We retrospectively reviewed 2894 patients with differentiated thyroid cancer who underwent primary thyroidectomy, identified 391 FNMTC cases, and compared the prevalence, surgical extension, and clinicopathologic features of FNMTC and SNMTC. A family history of thyroid cancer was noted in 391 patients (13.5%), with 85% having two affected relatives and 15% with ≥3 affected relatives. A sibling was affected in 52.9% of cases, and in 47.1%, both parent and child were affected. There were no significant between-group differences in sex, age, tumor size, extrathyroidal extension, or central lymph node metastases. Significantly more patients with FNMTC exhibited multifocal disease (p = 0.020) or benign nodules (p = 0.015). Lateral neck lymph node metastases were noted in 6.6% (SNMTC) and 9.7% (FNMTC, p = 0.021) of patients. Multifocality and combined benign masses were more frequently observed in patients with FNMTC in multivariate analysis. In the FNMTC group, seven experienced disease recurrence, with no mortality noted during follow-up. FNMTC is not more aggressive than SNMTC; however, FNMTC should be treated with total thyroidectomy because of the increased disease multifocality and the presence of benign nodules. Lateral neck lymph node metastases were more likely in patients with FNMTC, although we could not estimate prognosis. All patients with thyroid cancer should be checked for family disease history and undergo preoperative ultrasonography to determine the extent of node dissection and the need for total thyroidectomy.

MON-519 In Silico Analysis of rs1042522 and rs1042522 Polymorphic Variants of TP53 Gene

The TP53 gene encodes the p53 protein which is a nuclear phosphoprotein that plays a key role in cell cycle regulation, especially in the transition from G0 to G1. It is located on chromosome 17 at position p13.1 and found at very low levels in normal cells, but it is expressed in large quantities in damaged cells. The most frequent alterations in the TP53 gene are point mutations that cause alteration in the base sequence, resulting in a defective protein. The most frequent alteration occurs in codon 72 (rs1042522). P72R shows an exon 4 polymorphism of the TP53 gene where it there is a substitution of an arginine (Arg) by a proline (Pro). This variant is associated with sporadic thyroid cancer. In addition, codon 72 variants decrease p53’s ability to activate apoptosis and are associated with some autoimmune diseases like Graves’ disease. The codon variant 47 (rs1800371) P47S has a rare polymorphism in the p53 N-terminal transactivation domain that replaces the serine-like wild-type proline (Ser). This variant is associated with impaired pro-apoptotic p53 activity therefore also increasing the risk of cancer. In order to better understand the role of SNPs (rs1042522) and (rs1800371), based on data obtained from the NCBI dbSNP database and UniProt, we evaluated the effect of amino acid alteration on protein structure. We used bioinformatics tools such as SIFT (Sorting Intolerant from Tolerant), Align GVGD, PolyPhen-2, SNAP (Screening for nonacceptable polymorphisms), PANTHER (Protein Analysis Through Evalutionary Relationships), PredictSNP, nsSNPAnalyzer, PROVEAN, SNP & GO, PMut and MuPRO. Rs1042522 and rs1800371 bioinformatic analysis suggested that the amino acid change alters protein structure (Align GVGD tool), decreases the stability (MuPro tool) and function (SNAP) of the protein. SNPs & GO confirmed an association of these polymorphisms with different diseases. We conclude that SNPs rs1042522 and rs1800371 are important in the process of tumorigenesis, corroborating findings from our group and others that suggest that they difficult the action of p53 protein.

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.

Area Dose Response of Prevalent Childhood Thyroid Cancers after the Fukushima Nuclear Power Plant Accident

Background and Methods: After the Fukushima Nuclear Power Plant accident, thyroid ultrasound screening was carried out on all residents of ages≤18 years at the accident. In order to find the cause for thyroid cancer prevalence, area dose dependence of childhood thyroid cancer proportion in the first and second round screening (E-I, E-II), and in 6 years as a whole (E-I+II) was analyzed for external dose estimated by Fukushima Health Management Survey and effective dose estimated by UNSCEAR. The results were analyzed by the regression analysis of Microsoft Excel. Results: Thyroid cancer incidence within 4-6 years and prevalence in 6 years after the accident had tendency to increase with doses. In OM-model according to Ohira’s map, thyroid cancer prevalence in E-I+II after 6 years showed linear prevalence-effective dose response with positive coefficient 5.6 (CI=3.4-7.9) (cancer cases / 100,000 / mSv) in the 1.6–5 mSv range. In F-model according to official regional division, thyroid cancer proportion in E-II and E-I+II showed linear response to UNSCEAR effective dose with R2&gt;0.86 and p&lt;0.075. This correlation was higher than the correlation between external dose and effective dose with R2=0.71. Conclusion: The observed linear area dose relation in 6 years after exposure suggests highly probable association between childhood thyroid cancer in Fukushima and radiation exposure. UNSCEAR effective dose was found to give the best fit to linear regression line for E-II and E-I+II, irrespective of models. Linear dose response for reasonable area division can be a direct evidence for radiation related thyroid cancer because linear dose response cannot be observed in mass-screening for sporadic thyroid cancers.

Genetic Variants Implicate Dual Oxidase-2 in Familial and Sporadic Nonmedullary Thyroid Cancer

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), whereas low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513[A]. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline dual oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active, with increased production of reactive oxygen species. Furthermore, patients with sporadic thyroid cancer homozygous for rs965513[A] demonstrated higher DUOX2 expression than heterozygous rs965513[A/G] or homozygous rs965513[A]-negative patients. These data suggest that dysregulated hydrogen peroxide metabolism is a common mechanism by which high- and low-penetrance genetic factors increase thyroid cancer risk. SIGNIFICANCE: This study provides novel insights into the genetic and molecular mechanisms underlying familial and sporadic thyroid cancers.

Radiation-induced papillary thyroid cancer: is it a distinct clinical entity?

To present the current status of knowledge regarding radiation-induced papillary thyroid cancer (RIPTC), defining its epidemiologic, pathologic, and clinical characteristics, with ensuing possible therapeutic and prognostic consequences. Cumulative evidence shows that RIPTC resembles sporadic papillary thyroid cancer (PTC) of comparable age, both in terms of clinical-pathological features and prognosis. Therefore, more aggressive treatment does not seem to be required when managing RIPTC as its prognosis is comparable to that of never-irradiated patients. Radiation exposure in childhood is a well-documented risk factor for development of PTC. Therefore, increased exposure to medical or environmental radiation may be in part responsible, along with increased screening, of the recent burgeoning incidence of PTC. A specific morphological and molecular portrait of RIPTC is unlikely to exist. The more aggressive histologic and clinical features initially reported in radiation-induced cases are consistent with the expectations in nonradiation-related PTC of a comparable age. Aggressive histology, nodal, and distant metastases correlate with early age at onset rather than with radiation exposure. Although relapses are frequent in children, long-term cancer-specific mortality is approximately 1%, lower than that observed for adults and comparable between irradiated and nonirradiated cohorts. RIPTC does not require more aggressive surgery or more adjuvant treatments, as prognosis is as good as that of sporadic PTC when matched for stage and treatment received.

Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment

BackgroundThere are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. MethodsWe compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. ResultsA total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58). ConclusionPatients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.

Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels.

The BRAFV600E mutation is the most prevalent driver mutation of sporadic papillary thyroid cancers (PTC). It was previously shown that prenatal or postnatal expression of BRAFV600E under elevated TSH levels induced thyroid cancers in several genetically engineered mouse models. In contrast, we found that postnatal expression of BRAFV600E under physiologic TSH levels failed to develop thyroid cancers in conditional transgenic Tg(LNL-BrafV600E) mice injected in the thyroid with adenovirus expressing Cre under control of the thyroglobulin promoter (Ad-TgP-Cre). In this study, we first demonstrated that BrafCA/+ mice carrying a Cre-activated allele of BrafV600E exhibited higher transformation efficiency than Tg(LNL-BrafV600E) mice when crossed with TPO-Cre mice. As a result, most BrafCA/+ mice injected with Ad-TgP-Cre developed thyroid cancers in 1 year. Histologic examination showed follicular or cribriform-like structures with positive TG and PAX staining and no colloid formation. Some tumors also had papillary structure component with lower TG expression. Concomitant PTEN haploinsufficiency in injected BrafCA/+;Ptenf/+ mice induced tumors predominantly exhibiting papillary structures and occasionally undifferentiated solid patterns with normal to low PAX expression and low to absent TG expression. Typical nuclear features of human PTC and extrathyroidal invasion were observed primarily in the latter mice. The percentages of pERK-, Ki67- and TUNEL-positive cells were all higher in the latter. In conclusion, we established novel thyroid cancer mouse models in which postnatal expression of BRAFV600E alone under physiologic TSH levels induces PTC. Simultaneous PTEN haploinsufficiency tends to promote tumor growth and de-differentiation.

Abstract 400: Noncanonical role of SEC23B in thyroid carcinogenesis: Anemia gene meets cancer

Abstract Hereditary cancer syndromes serve as powerful models to uncover cancer-relevant genes. Cowden syndrome (CS), typically caused by germline PTEN mutations, is a heritable cancer syndrome with high risks of breast and thyroid cancers. However, there is a growing subset of CS without PTEN mutations. By exome sequencing cum family-studies, we identified heterozygous SEC23B variants in CS-associated and apparently sporadic thyroid cancer. Functional characterization revealed mutant CS-associated SEC23B led to endoplasmic reticulum (ER)-stress-mediated cell-colony formation and survival, growth and invasion, reflecting major hallmarks of cancer. Classically, SEC23B is a component of coat protein complex II (COPII) vesicles that transport secretory proteins from the ER to the Golgi apparatus. Germline homozygous or compound heterozygous loss-of-function SEC23B mutations cause Congenital Dyserythropoietic Anemia Type II (CDA II), resulting in decreased SEC23B levels. Intriguingly, our in vitro data does not recapitulate the CDA II-like decreased SEC23B protein expression, suggesting possible change-of-function effects in a cancer context. Here, we show mutant SEC23B exists within nucleoli, besides classical distribution at the ER/Golgi. This occurs in the absence of nucleolar localization of other COPII protein components and does not compromise canonical secretory function. Global transcriptomic and polysome profiling analyses reveal increased expression of ribosomal protein and translation-related genes, accompanied by enhanced translational capacity in mutant cells in response to ER stress. We also show mutant SEC23B directly binds to Upstream Binding Transcription Factor (UBF), concomitantly with increased UBF binding at the ribosomal DNA (rDNA) promoter region with ER stress. Unbiased proteomic analyses further show SEC23B, both wildtype and mutant, can interact with proteins in the ER stress and EIF2 signaling pathways. We validate through immunoprecipitation the binding interaction between SEC23B and UBA52, with notably increased binding with mutant SEC23B. UBA52 is ribosomal protein RPL40, known to regulate selective translation of stress-related transcripts, protein synthesis, and the cell cycle. Knockdown of SEC23B in vitro resulted in a concomitant decrease in protein levels of UBA52, further supporting that SEC23B and UBA52 are potentially co-regulated. All in all, our data suggest that SEC23B has non-canonical COPII-independent function, particularly within the ribosome biogenesis pathway, that may contribute to the pathogenesis of cancer-predisposition. Citation Format: Lamis Yehia, Ying Ni, Supriya Jindal, Ata Abbas, Anton A. Komar, Charis Eng. Noncanonical role of SEC23B in thyroid carcinogenesis: Anemia gene meets cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 400.