Germline and Somatic Mutations in Cyclin-Dependent Kinase Inhibitor Genes CDKN1A, CDKN2B, and CDKN2C in Sporadic Parathyroid Adenomas

Abstract

The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent 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 Cdknlb 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 neoplasia.

Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma

“…Nine polymorphisms were genotyped: CDKN1A (rs1801270 and rs1059234), CDKN1B (rs2066827 and rs34330), CDKN2A (rs11515), CDKN2B (rs2069426, rs3731239, and rs1063192), and CDKN2C (rs12885) using the TaqMan system (Applied Biosystems), as described previously (17). These SNPs were chosen because they have previously been associated with thyroid carcinoma or other tumor risks as described in Table 1 (13,15,16,20,21,22).…”

“…CDKN2A gene polymorphisms have largely been investigated in different types of cancers (20,22,35). The SNP (rs11515 -C98A) CDKN2A gene determines a non-synonymous serine-to-arginine substitution located in the 3 0 -UTR of exon 3 (36).…”

Recurrent ZFX mutations in human sporadic parathyroid adenomas

“…Previous investigations of the molecular pathogenesis of sporadic parathyroid adenomas identified recurrent, clonally selected driver mutations in the cyclin D1 (CCND1) proto-oncogene and MEN1 tumor suppressor gene, and a combination of rare germline variants and somatic alterations in several cyclin-dependent kinase inhibitor genes [2][3][4][5][6]. However, these derangements occur, collectively, in a minority of these tumors [2,3,7], and even when present are likely to cooperate with other driver lesions; thus multiple additional targets for tumorigenic mutation and future therapeutics undoubtedly exist.…”

Molecular and genetic features of primary hyperparathyroidism in young patients

“…J. CostaGuda и cоавт. [23] при исследовании 85 спорадиче-ских аденом ОЩЖ в 5 обнаружили гетерозиготные соматические замены в CDKIs, из них 3 -герми-нальные (1 -CDKN1A, 1 -CDKN2B, 1 -CDKN2C); все они были выявлены у пациентов старше 50 лет. Роль CDKIs в развитии наследственных форм ПГПТ требует дальнейшего изучения на бо льшей выборке пациентов.…”