Whole-exome sequencing studies have not established definitive somatic mutation patterns among patients with sporadic hyperparathyroidism (HPT). No sequencing has evaluated multiple endocrine neoplasia type 1 (MEN1)-related HPT. We sought to perform whole-exome sequencing in HPT patients to identify somatic mutations and associated biological pathways and tumorigenic networks.
Whole-exome sequencing was performed on blood and tissue from HPT patients (MEN1 and sporadic) and somatic single nucleotide variants (SNVs) were identified. Stop-gain and stop-loss SNVs were analyzed with Ingenuity Pathways Analysis (IPA). Loss of heterozygosity (LOH) was also assessed.
Sequencing was performed on 4 MEN1 and 10 sporadic cases. Eighteen stop-gain/stop-loss SNV mutations were identified in 3 MEN1 patients. One complex network was identified on IPA: Cellular function and maintenance, tumor morphology, and cardiovascular disease (IPA score = 49). A nonsynonymous SNV of TP53 (lysine-to-glutamic acid change at codon 81) identified in a MEN1 patient was suggested to be a driver mutation (Cancer-specific High-throughput Annotation of Somatic Mutations; P = .002). All MEN1 and 3/10 sporadic specimens demonstrated LOH of chromosome 11.
Whole-exome sequencing revealed somatic mutations in MEN1 associated with a single tumorigenic network, whereas sporadic pathogenesis seemed to be more diverse. A somatic TP53 mutation was also identified. LOH of chromosome 11 was seen in all MEN1 and 3 of 10 sporadic patients.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Surgery
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Positional cloning of the gene for multiple endocrine neoplasia-type 1.Science. 1997; 276: 404-407
- Hereditary hyperparathyroidism syndromes.J Clin Densitom. 2013; 16: 69-74
- Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study comparison of 106 MEn1/Zollinger-Ellison Syndrome Patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.Medicine. 2013; 92: 135-181
- An analysis of genotype–phenotype correlations and survival outcomes in patients with primary hyperparathyroidism caused by multiple endocrine neoplasia type 1: the experience at a single institution.Surg Today. 2013; 43: 894-899
- Molecular genetics of neuroendocrine tumors.Digestion. 2000; 62: 3-18
- Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies.Cancer. 2008; 113: 1807-1843
- Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.Mol Endocrinol. 2001; 15: 1653-1664
- Identification of somatic mutations in parathyroid tumors using whole-exome sequencing.J Clin Endocrinol Metab. 2012; 97: E1774-E1781
- Genotype-phenotype analysis in multiple endocrine neoplasia type 1.Arch Surg. 2002; 137: 641-647
- Multiple endocrine neoplasia syndrome: genetic basis for clinical management.Curr Opin Oncol. 2005; 17: 7-12
- Multiple endocrine neoplasms.Best Pract Res Clin Rheumatol. 2008; 22: 149-163
- Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.J Clin Endocrinol Metab. 2012; 97: E1995-E2005
- P53 tumour suppressor gene expression in hyperparathyroidism.Aust N Z J Surg. 1996; 66: 302-304
- Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism.J Clin Endocrinol Metab. 1998; 83: 2960-2963
- DAXX/ATRX, MEN1, and mTOR pathway s genes are frequently altered in pancreatic neuroendocrine tumors.Science. 2011; 331: 1199-1203
- Fast and accurate short read alignment with Burrows-Wheeler transform.Bioinformatics. 2009; 25: 1754-1760
- The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303
- Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.Nat Biotechnol. 2013; 31: 213-219
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res. 2010; 38: e164
- dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations.Hum Mutat. 2013; 34: E2393-E2402
- COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer.Nucleic Acids Res. 2011; 39: D945-D950
- Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools.Bioinformatics. 2012; 28: 421-422
- CRAVAT: cancer-related analysis of variants toolkit.Bioinformatics. 2013; 29: 647-648
- Causal analysis approaches in Ingenuity Pathway Analysis.Bioinformatics. 2014; 30: 523-530
- Haplotype-based profiling of subtle allelic imbalance with SNP arrays.Genome Res. 2013; 23: 152-158
Accepted: August 21, 2014
Financial support for Minerva Romero Arenas was provided in part by the Cornelius and Celia Dupre Fellowship in Surgical Endocrinology.
© 2014 Elsevier Inc. Published by Elsevier Inc. All rights reserved.