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Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family.

ABSTRACT: BACKGROUND: Familial papillary thyroid cancer (fPTC) is recognized as a distinct entity only recently and no fPTC predisposing genes have been identified. Several potential regions and susceptibility loci for sporadic PTC have been reported. We aimed to evaluate the role of the reported susceptibility loci and potential risk genomic region in a Chinese familial multinodular goiter (fMNG) with PTC family. METHODS: We sequenced the related risk genomic regions and analyzed the known PTC susceptibility loci in the Chinese family members who consented to join the study. These loci included (1) the point mutations of the BRAF and RET; (2) the possible susceptibility loci to sporadic PTC; and (3) the suggested potential fMNG syndrome with PTC risk region. RESULTS: The members showed no mutations in the common susceptible BRAF and RET genomic region, although contained several different heterozygous alleles in the RET introns. All the members were homozygous for PTC risk alleles of rs966423 (C) at chromosome 2q35, rs2910164 (C) at chromosome 5q24 and rs2439302 (G) at chromosome 8p12; while carried no risk allele of rs4733616 (T) at chromosome 8q24, rs965513 (A) or rs1867277 (A) at chromosome 9q22 which were associated with radiation-related PTC. The frequency of the risk allele of rs944289 (T) but not that of rs116909374 (T) at chromosome 14q13 was increased in the MNG or PTC family members. CONCLUSIONS: Our work provided additional evidence to the genetic predisposition to a Chinese familial form of MNG with PTC. The family members carried quite a few risk alleles found in sporadic PTC; particularly, homozygous rs944289 (T) at chromosome 14q13 which was previously shown to be linked to a form of fMNG with PTC. Moreover, the genetic determinants of radiation-related PTC were not presented in this family.

SUBMITTER: Liao S

PROVIDER: S-EPMC4015857 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family.

Liao Shunyao S Song Wenzhong W Liu Yunqiang Y Deng Shaoping S Liang Yaming Y Tang Zhenlin Z Huang Jiyuan J Dong Dandan D Xu Gang G

BMC endocrine disorders 20131021

<h4>Background</h4>Familial papillary thyroid cancer (fPTC) is recognized as a distinct entity only recently and no fPTC predisposing genes have been identified. Several potential regions and susceptibility loci for sporadic PTC have been reported. We aimed to evaluate the role of the reported susceptibility loci and potential risk genomic region in a Chinese familial multinodular goiter (fMNG) with PTC family.<h4>Methods</h4>We sequenced the related risk genomic regions and analyzed the known P ...[more]

PMID: 24144365

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Project description:CONTEXT:Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE:To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS:From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE:Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS:We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS:DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

Project description:BACKGROUND:Whereas 40 % to 70 % of papillary thyroid carcinomas (PTCs) are characterized by a BRAF mutation (BRAFmut), unified biomarkers for the genetically heterogeneous group of BRAF wild type (BRAFwt) PTCs are not established yet. Using state-of-the-art technology we compared RNA expression profiles between conventional BRAFwt and BRAFmut PTCs. METHODS:Microarrays covering 36,079 reference sequences were used to generate whole transcript expression profiles in 11 BRAFwt PTCs including five micro PTCs, 14 BRAFmut PTCs, and 7 normal thyroid specimens. A p-value with a false discovery rate (FDR) < 0.05 and a fold change > 2 were used as a threshold of significance for differential expression. Network and pathway utilities were employed to interpret significance of expression data. BRAF mutational status was established by direct sequencing the hotspot region of exon 15. RESULTS:We identified 237 annotated genes that were significantly differentially expressed between BRAFwt and BRAFmut PTCs. Of these, 110 genes were down- and 127 were upregulated in BRAFwt compared to BRAFmut PTCs. A number of molecules involved in thyroid hormone metabolism including thyroid peroxidase (TPO) were differentially expressed between both groups. Among cancer-associated molecules were ERBB3 that was downregulated and ERBB4 that was upregulated in BRAFwt PTCs. Two microRNAs were significantly differentially expressed of which miR492 bears predicted functions relevant to thyroid-specific molecules. The protein kinase A (PKA) and the G protein-coupled receptor pathways were identified as significantly related signaling cascades to the gene set of 237 genes. Furthermore, a network of interacting molecules was predicted on basis of the differentially expressed gene set. CONCLUSIONS:The expression study focusing on affected genes that are differentially expressed between BRAFwt and BRAFmut conventional PTCs identified a number of molecules which are connected in a network and affect important canonical pathways. The identified gene set adds to our understanding of the tumor biology of BRAFwt and BRAFmut PTCs and contains genes/biomarkers of interest.

Project description:BackgroundThe most appropriate surgical procedure for multinodular goiter (MNG) remains under debate. Incidental thyroid carcinoma (ITC) is often identified on histopathological examination after thyroidectomy performed for presumed benign MNG.Aim of the studyThe aim of the study was to determine the value of radical surgery for MNG patients considering the prevalence of ITC diagnosed postoperatively.Materials and methodsWe conducted retrospective analysis of the medical records of 2,306 patients surgically treated for MNG between 2008 and 2013 at one center. None of the patients presented with any suspicion of malignancy, history of familial thyroid cancer, multiple endocrine neoplasia syndrome or previous head or neck radiation exposure.ResultsAmong the 2,306 MNG patients, ITC was detected in 49 (2.12%) (44 women and 5 men, with average ages of 52.2 (21-79) and 55.6 (52-62), respectively). Papillary thyroid carcinoma was significantly more frequently observed than other types of ITC (p<0.00001). Among the MNG patients, 866 (37.5%) underwent total/near total surgery, 464 (20.1%) received subtotal thyroidectomy, and 701 (30.3%) received the Dunhill operation. The remaining 275 (11.9%) patients underwent a less radical procedure and were classified as "others." Among the 49 (100%) patients with ITC, 28 (57.1%) underwent radical surgery. Another 21 (42.9%) patients required completion surgery due to an insufficient primary surgical procedure. A total of 21 (2.42%) patients in the total/near total surgery group were diagnosed with ITC, as well as 16 (2.48%) in the subtotal thyroidectomy group and 12 (1.71%) in the Dunhill operation group; 21 (100%), 4 (25%) and 3 (25%) of these patients, respectively, underwent radical surgery; thus, 0 (0%), 12 (75%) and 9 (75%) required completion surgery. The prevalence rates of ITC were comparable between the radical and subtotal surgery groups (2.42% and 3.44%, respectively, p = 0.4046), and the prevalence was higher in the radical surgery group than in the Dunhill operation group (2.42% and 1.71%, respectively, p = 0.0873). A significant difference was observed between the group of patients who underwent total/near total surgery, among whom all of the patients with ITC (100%) received primary radical surgery, and the groups of patients who received the subtotal and Dunhill operations, among whom only 25% of the patients with ITC in each group received primary radical surgery (p<0.0001).ConclusionsMore radical procedures for MNG result in a lower risk of reoperation for ITC. The prevalence of ITC on postoperative histopathological examination should determine the extent of surgery in MNG patients. In the future, total/near total thyroidectomy should be considered for MNG patients due to the increased prevalence of ITC to avoid the necessity for reoperation.

Project description:Synopsis for table of contentsAn exceptional number of synchronous MTC/PTC in the same thyroid gland is presented. This may be the most numerous case series reported in the literature. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes and the clinical and pathological aspects as well as the results are presented.Background and objectivesThe synchronous occurrence of multiple neoplastic processes in the thyroid gland is unusual. We investigated the clinicopathological features of 30 medullary thyroid carcinomas (MTC) in association with papillary (PTC).MethodRetrospective analysis of operated patients for thyroid tumors. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes: (type I) True mixed MTC/PTC, MTC and PTC closely intermingled. (Type II) Collision MTC/PTC, i.e. tumors that meet at the same site, invade each other and appear as a single mass in the thyroid gland, i.e. MTC and PTC merge. (Type III) Synchronous anatomically separate tumors in the same thyroid lobe, i.e. separated from each other by non-tumorous thyroid parenchyma. (Type IV) Synchronous tumors occurring in separate anatomical lobes or in the isthmus. Clinical and pathological data were reviewed. Location: Department of thyroid surgery, China-Japan Union Hospital, Jilin University. Time frame: 14 years (June 2008-November 2022).ResultsThirty patients were identified with an overall prevalence of 28621 (0.1%). 17 (56.7%) were male, 13 (43.3%) female, mean age 51.3 ± 11.0 years, mean BMI 23.6 ± 3.6kg/m2. Mean duration of symptoms was 11.2 ± 18.4 months. Mean calcitonin level was 133.7 ± 196.4 pg/ml. Fine needle aspiration (FNA) was offered in 21 cases: 9 (42.9%) were suspected carcinoma, 9 (42.9%) PTC, 1 (4.8%) MTC, 2 (9.4%) MTC/PTC. Pathology revealed type I 4 (13.3%), type II 2 (6.7%), type III 14 (46.7%), type IV 10 (33.3%). The mean diameter of MTC was 1.6 ± 2.0cm, 18 (60%) were micro-MTC. The mean diameter of PTC was 0.9 ± 1.9 cm, 26 (86.7%) were micro-PTC. In 16 (53.3%) micro-PTC/-MTC occurred in synchronous sequence. Four patients had a recurrence: 2 had to be re-operated due to MTC recurrence, 2 died due to distant metastases (bone, liver).ConclusionWe report an exceptional number of MTC/PTC in the same thyroid gland. This may be the most numerous case series reported in the literature. The clinical and pathological aspects as well as the results are presented.

Dataset Information

Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family.

Publications

Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family.

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