Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours

Abstract

The majority of pituitary tumours are monoclonal in origin and arise sporadically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1). Whilst a multi-step aetiology involving both oncogenes and tumour suppressor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumours have been shown to harbour allelic deletion on 11q13, which is the location of the recently cloned MEN1 gene. We investigated 23 sporadic pituitary tumours previously shown to harbour allelic deletion on 11q13 with the marker PYGM centromeric and within 50 kb of the MEN1 locus. In addition, the use of intragenic polymorphisms in exon 9 and at D11S4946 , and of telomeric loci at D11S4940 and D11S4936 , revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene. However, the overall pattern of loss in informative cases was indicative of non-contiguous deletion that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DNA, did not reveal mutation(s) in any of the 23 tumours studied. A benign polymorphism in exon 9 was encountered at the expected frequency, and in seven patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reaction analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that gene silencing is unlikely to be mechanistic in sporadic pituitary tumorigenesis, they do not exclude changes in the level or stability of the transcript or translation to mature protein. Our study would support and extend very recent reports of a limited role for mutations in the MEN1 gene in sporadic pituitary tumours. Alternatively, these findings may point to an, as yet, unidentified tumour suppressor gene in this region. © 1999 Cancer Research Campaign

Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study

“…Moreover, we have been able to compare the data obtained in MEN 1 patients with those from 110 non-MEN1 patients with pituitary adenomas, matched for age, year of diagnosis, and follow-up period. On the basis of several reports that have shown that MEN1 germline mutation testing was not useful in isolated sporadic pituitary adenomas (21)(22)(23), no control subject had MEN1 mutation testing. However, each control subject had no other endocrine lesion than the pituitary tumor at the time of diagnosis, as during the follow-up period, and no family history of multiple endocrine neoplasia, attesting that control subjects were non-MEN1 patients.…”

Novel Molecular Signaling and Classification of Human Clinically Nonfunctional Pituitary Adenomas Identified by Gene Expression Profiling and Proteomic Analyses

“…A minority is part of an autosomaldominant syndrome, multiple endocrine neoplasia type 1 (MEN1), which is associated with mutations in the MEN1 tumor suppressor gene. Others are associated with loss of heterozygosity on the 11q13 chromosome (2,(8)(9)(10). A dominant mutation occurs in the Gas gene in f30% of somatotrophinomas, but this mutation is rare in other pituitary tumors (2,11,12).…”

Isolated Familial Somatotropinomas: Establishment of Linkage to Chromosome 11q13.1–11q13.3 and Evidence for a Potential Second Locus at Chromosome 2p16–121

“…The combined results of 5 published reports reveal that mutations in the coding region or exon-intron boundaries of MEN-1 were present in only 8% (2 of 25) of sporadic somatotropinomas with LOH at 11q13 (30 -34). In addition, RT-PCR of total mRNA from 10 of these 23 tumors with LOH, but no MEN-1 mutation, revealed that the MEN-1 transcript was detectable in all (31,34,35), supporting the view that mutations in noncoding regions of MEN-1 or epigenetic mechanisms are unlikely to be involved in the pathogenesis of most somatotropinomas.…”