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

The majority of pituitary tumours are monoclonal in origin and arise sporad ically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1 ). Whilst a multi-step aetiology involving both oncogenes and tumour suppre ssor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumo urs have been shown to harbour allelic deletion on 11q13, which is the loca tion of the recently cloned MEN1 gene. We investigated 23 sporadic pituitar y tumours previously shown to hart,our allelic deletion on 11q13 with the m arker 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 telomeri c loci at D11S4940 and D11S4936, revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene, However, the overall p attern of loss in informative cases was indicative of noncontiguous deletio n that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DN A, did not reveal mutation(s) in any of the 23 tumours studied. A benign po lymorphism in exon 9 was encountered at the expected frequency, and in seve n patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reac tion analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that g ene silencing is unlikely to be mechanistic in sporadic pituitary tumorigen esis, they do not exclude changes in the level or stability of the transcri pt or translation to mature protein. Our study would support and extend ver y recent reports of a limited role for mutations in the MEN1 gene in sporad ic pituitary tumours, Alternatively these findings may point to an, as yet, unidentified tumour suppressor gene in this region.