Germline and Somatic Mutations in CyclinDependent

Authors: Jessica CostaGuda ChenPang Soong Vaishali I Parekh Sunita K Agarwal Andrew Arnold

Publish Date: 2013/05/29

Volume: 4, Issue: 5, Pages: 301-307

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Abstract

The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood The possible role of cyclindependent kinase inhibitor CDKI genes was raised by recognition of cyclin D1 as a parathyroid oncogene identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1 that in rodents mutation in Cdkn1b caused parathyroid tumors and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B encoding p27kip1 in sporadic human parathyroid adenoma We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A CDKN1C CDKN2A CDKN2B CDKN2C and CDKN2D encoding p21 p57 p14ARF/p16 p15 p18 and p19 respectively contribute to the development of typical parathyroid adenomas In a series of 85 sporadic parathyroid adenomas direct DNA sequencing identified alterations in five adenomas 6  Two contained distinct heterozygous changes in CDKN1A one germline and one of undetermined germline status one had a CDKN2B germline alteration accompanied by loss of the normal allele in the tumor LOH two had variants of CDKN2C one somatic and one germline with LOH Abnormalities of three of the mutant proteins were readily demonstrable in vitro Thus germline mutations/rare variants in CDKN1A CDKN2B and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasiaWe wish to thank Ms Kristin Corrado for expert technical assistance This work was supported in part by grants DHHS/NIDCR 5 T32DE07302 and 1 F32DE021307 to JCG from the National Institutes of Health the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases SKA Project number 1ZIADK07503503 and by the MurrayHeilig Fund in Molecular Medicine

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