MEN1 Mutations in Hürthle Cell (Oncocytic) Thyroid Carcinoma

Abstract

Context and Objective: 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. Design and Patients: 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. Results: 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. Conclusion: 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.

ROS-induced near-homozygous genomes in thyroid cancer

“…Using a new method for DNA content analysis (Corver et al 2005) in combination with single nucleotide polymorphism (SNP) technology (Corver et al 2008), we demonstrated that many FTC-OV actually show a near-homozygous genome (NHG) in which a phase of near-haploidization is followed by endoreduplication or genome doubling of the entire NHG (Corver et al 2012(Corver et al , 2014. Our observations regarding an NHG have been confirmed by others (Wagle et al 2014, Kasaian et al 2015. Furthermore, retention of chromosome 7, a hallmark for FTC-OV, was recently attributed to genomic imprinting of genes on both paternal and maternal alleles that are important for tumor cell survival (Boot et al 2016).…”

Preoperative Diagnosis of Neoplastic or Malignant Hürthle Cell Lesions: A Chimera?

“…Other studies, however, describe differences in their behavior and oncogene expression [10-12]. For example, Parikh et al [13] showed a higher rate of distant metastases in HC carcinoma.…”

Overview of Hurthle cell carcinoma of thyroid

“…the peroxisome proliferator-activated receptor γ (PPARG) gene, and the neurotrophic tyrosine kinase receptor, type 3 (NTRK3) gene. Kasaian et al found multiple endocrine neoplasia (MeN-1) gene mutations in 4% of HCC [49] . Another genetic mutation, human TeRT (hTeRT), is detected by immunohistochemistry, and the telomere length can be determined by tissue quantitative fluorescence in-situ hybridization.…”

“…MeN1, multiple endocrine neoplasia [49] Loss of function to produce the tumor suppressor protein, called menin which is required for apoptosis…”