Interpretation

As for any clinical molecular genetic test, the ability to identify a specific gene mutation to correlate with the disease status of an affected individual depends on the sensitivity of the assay. A well-defined clinical phenotype is essential for accurate interpretation and reporting of molecular test results to the healthcare professional. Genotype-phenotype correlations are either imperfect or nonexistent for these disorders. Both MEN1 and MEN2 are inherited in autosomal dominant patterns; thus, a single germline mutation confers predisposition for these cancer syndromes. At the cellular level, MENl-associated tumors are caused by inactivation of both copies of this tumor suppressor gene, while mutation of a single copy of RET produces a gain of function, dominantly expressed effect.11

About 80% of patients with MEN1 will have a germline mutation identified in the MEN1 gene coding for the menin protein.1,3 MEN1 germline mutations also have been identified in nearly two thirds of patients with sporadic MEN1.10 There is presently no specific genotype-phenotype association of MEN1 mutations to predict the clinical course or onset of this disease. More than 400 different mutations have been described in the MEN1 literature, and some of these have been reported in multiple, independent kindreds. Characterization of these same genetic variations in newly diagnosed individuals supports the role of the mutant allele in the disease etiology and is very helpful to the molecular pathology interpretation. As in many genetic syndromes, molecular identification of a pathogenic MEN1 mutation in a family member with clinical features of MEN1 is most significant in the risk assessment of other first-degree relatives.

As reviewed by Guo and Sawicki, MEN1 mutations are not limited to patients with MEN1.10 A significant number of sporadic endocrine tumors also may harbor MEN1 mutations but not with the same prevalence as the same types of tumors in the syndromic cases. MEN1 mutations do not provide clinically useful information for sporadic tumor staging.11 While one third of MEN1 patients will develop pituitary tumors and carry germline MEN1 mutations, only about 1% of sporadic pituitary tumors carry MEN1 mutations. The frequency of MEN1 mutations also differs between different types of pancreatic endocrine tumors. In sporadic gastrinomas, the rate of MEN1 mutations is 37% in contrast to 15% of sporadic nongastrin-oma pancreatic tumors. Insulinomas, another pancreatic endocrine tumor of MEN1, have been characteristic of the MEN1 knockout mice,18 but MEN1 mutations have not been found in sporadic insulinomas.19 Clearly the role of menin in familial and sporadic tumors is not the same. Sporadic parathyroid and pituitary adenomas with no detectable MEN1 mutation may be characterized as phe-nocopies of MEN1, particularly when there is no family history of MEN1.10

Information about the penetrance and expressivity of the mutations in MEN1 described to date suggests that there is nearly 100% risk for MEN1 in carriers of the same familial mutation by the age of 60 years.3 Mutations leading to truncated protein expression create loss of functional menin protein. Missense mutations may disrupt menin interaction with cell growth regulatory molecules or its cellular localization. These mutations also may decrease the stability of menin protein or lead to its degradation. This is largely speculative at this time because the exact function of menin is unknown.

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