Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas

TY - JOUR

T1 - Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas

AU - Newey, Paul J.

AU - Nesbit, M. Andrew

AU - Rimmer, Andrew J.

AU - Attar, Moustafa

AU - Head, Rosie T.

AU - Christie, Paul T.

AU - Gorvin, Caroline M.

AU - Stechman, Michael

AU - Gregory, Lorna

AU - Mihai, Radu

AU - Sadler, Greg

AU - McVean, Gil

AU - Buck, David

AU - Thakker, Rajesh V.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Context: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in Objective: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.Design: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.Results: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (similar to 35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.Conclusions: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations. (J Clin Endocrinol Metab 97: E1995-E2005, 2012)

AB - Context: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in Objective: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.Design: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.Results: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (similar to 35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.Conclusions: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations. (J Clin Endocrinol Metab 97: E1995-E2005, 2012)

KW - PRIMARY HYPERPARATHYROIDISM

KW - SOMATIC MUTATION

KW - CANCER GENOMES

KW - MEN1 GENE

KW - TUMORS

KW - POT1

KW - DNA

KW - HETEROZYGOSITY

KW - EPIDEMIOLOGY

KW - ACTIVATION

U2 - 10.1210/jc.2012-2303

DO - 10.1210/jc.2012-2303

M3 - Article

C2 - 22855342

SN - 0021-972X

VL - 97

SP - E1995-E2005

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 10

ER -