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Comparative Study
. 2014 Dec;156(6):1351-7; discussion 1357-8.
doi: 10.1016/j.surg.2014.08.073. Epub 2014 Nov 11.

Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients

Minerva Angélica Romero Arenas  1 , Richard G Fowler  2 , F Anthony San Lucas  2 , Jie Shen  2 , Thereasa A Rich  1 , Elizabeth G Grubbs  1 , Jeffrey E Lee  1 , Paul Scheet  2 , Nancy D Perrier  1 , Hua Zhao  3
Affiliations
Comparative Study

Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients

Minerva Angélica Romero Arenas et al. Surgery. 2014 Dec.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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Figures

Fig 1
Fig 1
Network identified on Ingenuity Pathways Analysis (IPA) analysis for stop-gain single nucleotide variants (SNVs) detected in 3 patients with multiple endocrine neoplasia type 1 (MEN1)-related hyperparathyroidism (HPT). The network centers on the protein ubiquitin C.
Fig 2
Fig 2
Allelic imbalance events across the genome of multiple endocrine neoplasia type 1 (MEN1) and sporadic hyperparathyroidism (HPT) patients (black bars). MEN1 samples are labeled A and sporadic samples are labeled C. Loss of heterozygosity (LOH) of chromosome 11 is seen in all 6 MEN1 samples and 3 of 10 sporadic adenomas. Samples C4, C8, and C10 (not shown) exhibited no chromosome LOH events.
See this image and copyright information in PMC

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