Dataset Information

MEN1 mutations in Hurthle cell (oncocytic) thyroid carcinoma.

ABSTRACT: Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management.Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene.Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors.Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.

SUBMITTER: Kasaian K

PROVIDER: S-EPMC4399284 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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MEN1 mutations in Hürthle cell (oncocytic) thyroid carcinoma.

Kasaian Katayoon K Chindris Ana-Maria AM Wiseman Sam M SM Mungall Karen L KL Zeng Thomas T Tse Kane K Schein Jacqueline E JE Rivera Michael M Necela Brian M BM Kachergus Jennifer M JM Casler John D JD Mungall Andrew J AJ Moore Richard A RA Marra Marco A MA Copland John A JA Thompson E Aubrey EA Smallridge Robert C RC Jones Steven J M SJ

The Journal of clinical endocrinology and metabolism 20150127 4

<h4>Context and objective</h4>Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide be ...[more]

PMID: 25625803

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Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20).Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways.All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent).We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. MICROARRAYS: Data are made available at GEO (GSE31828).

Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). Methods Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. Results All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). Conclusions We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research.

Project description:PurposeRadioactive iodine (RAI) is widely used for adjuvant therapy after thyroidectomy, while its value for thyroid cancer has been controversial recently. The primary objectives of this study were to clarify the influence of Radioactive iodine (RAI) on the survival in rare oxyphilic subtype of thyroid cancer (Hürthle cell carcinoma, HCC).MethodsPatients diagnosed with oxyphilic thyroid carcinoma from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results Program database. The Kaplan-Meier method was used to compare overall survival (OS) and cancer-specific survival (CSS) among patients who had adjuvant RAI use or not. Univariate and multivariate Cox proportional hazard models were performed for survival analysis, and subsequently visualized by nomogram.ResultsIn all, 2,799 patients were identified, of which 1529 patients had adjuvant RAI use while 1,270 patients had not. Based on multivariate Cox analysis, the RAI therapy confers an improved OS for HCC patients (HR = 0.57, 95% CI [0.44-0.72], P < 0.001), whereas it has no significant benefit in the survival analysis regarding CSS (HR = 0.79, 95% CI [[0.47-1.34], P = 0.382). In a subgroup analysis, the same survival benefit of RAI treatment on OS, but not CSS was observed among patients stratified by AJCC stage and tumor extension. Nevertheless, patients with regional lymph node metastasis benefited from RAI therapy both in OS and CSS (P < 0.001, respectively). Furthermore, nomograms used for predicting long term survival of HCC patients exhibited a better prediction power for OS compared with traditional tumor, nodal and metastatic (TNM) stage made by American Joint Committee on Cancer (AJCC) (C-index = 0.833 of the nomogram model vs. 0.696 of the AJCC system).ConclusionsThis study suggests that RAI therapy is significantly associated with improved OS in patients with Hürthle cell carcinoma. However, there was no association between treatment with radioiodine and CSS, possibly due to small number of deaths that were related to HCC.

Dataset Information

MEN1 mutations in Hurthle cell (oncocytic) thyroid carcinoma.

Publications

MEN1 mutations in Hürthle cell (oncocytic) thyroid carcinoma.

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