Identification of Somatic Mutations in Parathyroid Tumors Using Whole-exome Sequencing

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2012 Jun 29

PMID 22740705

Citations 81

Authors

M Kyle Cromer

Lee F Starker

Murim Choi

Robert Udelsman

Carol Nelson-Williams

Richard P Lifton

Tobias Carling

Affiliations

Soon will be listed here.

Abstract

Context: The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined.

Objective: The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing.

Design: Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas.

Results: Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing.

Conclusion: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.

Citing Articles

Molecular Pathophysiology of Parathyroid Tumorigenesis-The Lesson from a Rare Disease: The "MEN1 Model".

Brunetti A, Cosso R, Vescini F, Falchetti A Int J Mol Sci. 2024; 25(21).

PMID: 39519139 PMC: 11545851. DOI: 10.3390/ijms252111586.

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma.

Xu Q, La T, Ye K, Wang L, Wang S, Hu Y Clin Transl Med. 2024; 14(6):e1734.

PMID: 38888967 PMC: 11185127. DOI: 10.1002/ctm2.1734.

Syndromic MEN1 parathyroid adenomas consist of both subclonal nodules and clonally independent tumors.

Brautigam K, Nesti C, Riss P, Scheuba C, Niederle B, Grob T Virchows Arch. 2024; 484(5):789-798.

PMID: 38244045 PMC: 11106174. DOI: 10.1007/s00428-023-03730-3.

Molecular Genetic Aspects of Sporadic Multiglandular Primary Hyperparathyroidism.

Vcelak J, Serkova Z, Zajickova K Physiol Res. 2023; 72(S4):S357-S363.

PMID: 38116772 PMC: 10830163. DOI: 10.33549/physiolres.935253.

Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing.

Li L, Sheng Q, Zeng H, Li W, Wang Q, Ma G Front Endocrinol (Lausanne). 2023; 14:1221060.

PMID: 37854190 PMC: 10579901. DOI: 10.3389/fendo.2023.1221060.

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