Genetic and immunohistochemical study

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Pancreatic endocrine tumors (PETs) are rare neoplasms of complex entity that can arise sporadically or as a part of the hereditary sindrome multiple endocrine neoplasia type 1 (MEN1), caused by germline alterations in MEN1 gene. Indeed, the most common anomaly encountered both in familial and sporadic PETs is MEN1 gene inactivation due to mutation and loss of the second allele. MEN1 gene maps on chromosome 11q13 and encodes for a ubiquitously expressed protein, named menin. Allelic losses (loss of heterozygosity, LOH) in chromosome 11q13, which includes the locus of MEN1 gene, are found in 46% of sporadic PETs. On the other hand, the rate of genetic abnormality decreases when searching for somatic MEN1 gene mutations. In this study, we have analyzed the largest panel of sporadic PETs in the attempt to better understand the involvement of MEN1 in the pathogenesis of these tumors. To clarify the role of this gene, we analyzed the alterations of MEN1 in 64 non-functioning (NF-PETs) and 24 functioning (F-PETs) tumors. The overall mutation rate of sporadic PETs was 25% (22/88). Somatic mutations were observed in 19 (29.7%) NF-PETs and in 3 (17%) insulinomas. Taken together all mutations are likely to result in a functional loss of menin either by loss of its nuclear localization or affecting its ability to interact with different proteins. Also, we investigated menin protein expression in a series of tissue microarrays, including many of the cases screened for genetic alterations. Finally, our results show that: i) about one-third of sporadic NF-PETs are characterized by MEN1 gene alterations; ii) there is no correlation between MEN1 mutations and clinical-pathological parameters; iii) menin nuclear expression correlates with both mRNA levels and truncating gene mutations; iv) there is a positive correlation between cytoplasmic protein expression and a shorter time to progression. MEN1 mutation is a major event in sporadic PETs confirming its importance in the development of this disease. However, the presence of mutation as well as the lack of protein expression does not correlate with a definite clinical biological phenotype, suggesting that loss of menin might be an early and common event in the pathogenesis of this neoplasia.