Discovery of germline and somatic mutations in apparently sporadic parathyroid tumours

Abstract

Background To discriminate between sporadic and hereditary parathyroid tumours and characterize multiple endocrine neoplasia type 1 (MEN1) somatic mutations, MEN1 gene mutations were examined in patients with apparently sporadic parathyroid tumours. Methods DNA was extracted from fresh frozen parathyroid tumour specimens from 112 patients, as well as from peripheral blood leucocytes (PBL) from 60 of the 112 patients. Sequencing was performed to examine exons 2–10 of the MEN1 gene for mutations. In addition, exons 10 and 11 of the RET gene were sequenced. Results MEN1 mutations were found in 25 (22 per cent) of the 112 patients. Two patients had two simultaneous point-mutations. A total of 27 mutations were characterized, 24 of which have not been reported previously. There were seven nonsense mutations, ten frameshift mutations, two splice-site deletions, five missense mutations and three in-frame mutations. Nineteen mutations resulted in truncation of menin protein. Germline MEN1 mutations were found in three of 60 patients who had no family history of endocrine tumours associated with MEN1, and these patients were identified as MEN1 gene family probands. No somatic or germline RET exon 10 and 11 mutations were found in this series. Conclusion These findings suggest that MEN1 gene mutation may be associated not only with endocrine tumours of affected patients with MEN1 but also with sporadic parathyroid tumours. MEN1 gene analysis can distinguish inheritable from non-inheritable parathyroid tumours and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumours is necessary before parathyroid surgery.

Recurrent ZFX mutations in human sporadic parathyroid adenomas

“…This MEN1 intragenic mutation frequency of ~11% is in agreement with earlier literature, which found a range between 12-20% [11][12][13], and contrasts with recent suggestions that the frequency might be considerably higher (up to 35-40%) [8,9,[17][18][19][20]. No mutations in genes recently proposed to be implicated in parathyroid adenoma tumorigenesis, such as CTTNB1, EZH2 and POT1, were identified, attesting to the rarity of these candidate genes' potential contributions [21].…”

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

“…The mouse menin cDNA was obtained by PCR amplification using a spleen cDNA library as the template as previously described. (15) The previously reported variant sequences and their corresponding phenotypes were according to the references as follows: P12L, L22R, K119del, H139D, A160P, A242V, A309P, T344R, E363del, W436R and R460X; (16) G28A; (17) D153V and A411P; (18) G156C, F364C and F447L; (19) A160T and D418N; (20) R171W and E366D; (21) V184E; (9) T197I and Y353del; (22) W220L and Y351N; (23) R229L; (24) S253W and E274A; (11) E255K; (10) Q260P; (25) L264P and L267P; (26) P277H; (27) G305D; (12) H317Y; (14) P320R; (28) P320L; (29) L414del; (30) and S555N. (31) The expression vector pCMV-BICEP-4 (Sigma, St. Louis, MO, USA), designed to allow translation of two proteins from one bicistronic mRNA, was used for transient co-expression of N-terminal FLAG-tagged and Myc-tagged menin proteins.…”

“…(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathyroidism (FIHP), (8)(9)(10) defined as familial primary hyperparathyroidism not associated with other diseases, and in a few patients clinically diagnosed as having sporadic parathyroid tumor. (11) The latter situation is called apparently sporadic parathyroid tumor (ASPT) because of its heritable, potentially familial nature. Because parathyroid tumor is the most frequent and earliest clinical expression of MEN1, patients with FIHP or ASPT carrying germline MEN1 mutations might develop full manifestations of MEN1.…”

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

“…134 Of individuals with two MEN1 manifestations, 26% had a MEN1 mutation. 135 Because of the relatively low mutation detection rates in sporadic cases, 134,[136][137][138][139] no single MEN1-associated tumor is sufficient to warrant genetic counseling referral, with the exception of gastrinoma, of which 20% are due to MEN1 mutations. 140 For this guideline, we are adopting the recommendation of the MEN1 International Consensus 134 and the MEN1 Clinical Practice Guidelines.…”