The significance of MEN1 mutations in Pituitary Carcinomas

KEYWORDS::

• MEN1
• pituitary adenoma
• pituitary carcinoma
• prolactinoma

MEN1 syndrome

“…although recent clinical cases reported MEN1-related pituitary carcinomas, there is still no evidence for a higher risk of pituitary carcinoma in MEN1 syndrome compared with the general population…”

Multiple endocrine neoplasia Type I (MEN1) syndrome is characterized by the onset of endocrine tumors, in particular parathyroid, digestive (predominantly gastrinoma) and anterior pituitary tumors. The incidence of the disease is estimated to be 0.25% worldwide and the syndrome can affect all age groups [1]. Patients can also develop, at a lesser degree, adrenal tumors, lipomas, meningiomas, facial angiofibromas and collagenomas. MEN1 syndrome belongs to a family of autosomal dominant disorders with a high degree of penetrance such that primary hyperparathyroidism is diagnosed in nearly all patient after the fifth decade of life [1].

The gene responsible for the syndrome (MEN1), known as a tumor suppressor gene, was identified for the first time in 1997 [2]. It is located on chromosome 11q13 and encodes MEN1, a 610-amino acid protein that finely regulates transcription, proliferation and gene expression within the cell [3]. However, its exact role in tumorigenesis still remains under investigation, given the many molecular partners with which MEN1 interacts within a complex network.

The onset of the syndrome requires inheritance of a germline mutation of MEN1 and a somatic mutation (most of the time a deletion) in the tumor DNA, leading to loss of heterozygosity. These sequences are consistent with the definition of a tumor suppressor role for MEN1, according to the Knudson two-hit hypothesis [4]. While more than 1300 germline mutations within the whole sequence of the gene have been identified [4], no genotype–phenotype correlation is currently known. Nevertheless, the higher risk of death in MEN1-affected patients was recently found to be associated with mutation in the JunD interacting domains [5].

MEN1 & pituitary adenomas

The prevalence of pituitary adenomas (PAs) in MEN1 syndrome varies from 10 to 70% depending on the series considered [6]. While it is recommended to screen PA in patients with MEN1 syndrome by hormonal assessment and pituitary MRI [1], less is known about the inverse situation: should we screen MEN1 mutations in each patient with PA? The answer depends of the context. The prevalence of MEN1 syndrome among all patients diagnosed with isolated PA is less than 3% [7], explaining why MEN1 genetic screening is not recommended in this population of patients [1]. On the other hand, MEN1 mutations may be identified in nearly 8% of patients diagnosed with PA and at least one other lesion of the MEN1 syndrome spectrum [8]. Given this prevalence, screening for MEN1 mutations is highly recommended in this situation.

However, are there specific features of isolated PA that justify MEN1 genetic screening? PA can occur as the first clinical manifestation of MEN1 syndrome in nearly 15% of patients with a prevalence and probability for developing pituitary tumors significantly higher in females [9]. Usually, the predominant phenotype is prolactinoma, followed by nonfunctioning PA, growth hormone-secreting PA and adrenocorticotropic hormone-secreting PA [10]. A previous case–control study showed that the proportion of macroadenomas was higher in the case of MEN1 mutations compared with cases without (85 vs 42%; p < 0.001) [11] and patients with MEN1 mutations harboring macroadenomas tend to be younger at diagnosis [12]. Taken together, these results suggest that in the whole population of patients with sporadic and isolated PA, very young patients with macroadenoma may be at higher risk of MEN1 mutations. To further investigate this point, we recently conducted a clinical study including 174 young patients (age ≤30 years) diagnosed with sporadic (i.e., without familial history of PA) and isolated (i.e., without any MEN1-related lesion) macroadenoma. In the whole cohort, the prevalence was quiet low (nearly 3.5%), but reached 5.4% in the case of isolated macroprolactinomas and 6% in the pediatric population (age ≤18 years), prompting us to suggest a systematic screening of MEN1 in these subpopulations of patients [13]. This attitude can be supported by the consequences, in terms of comorbidities, of a positive screening in each (young) patient given the penetrance of the disease. Moreover, in MEN1 cases, a well-described lesser sensitivity to dopamine agonist (DA) therapy of prolactinoma tumors has been described; therefore, other therapies, such as surgery or radiotherapy, should be of interest alongside DA in these specific cases [11]. Finally, positive screening for the gene, given its dominant inheritance, should also be systematically conducted to look for asymptomatic family carriers for a preventative approach.

Do MEN1 mutations promote pituitary carcinoma onset?

Benign pituitary tumors account for nearly 15% of all intracranial neoplasms, but only a small proportion of them will be classified as aggressive tumors or pituitary carcinomas. The latter accounts for less than 0.2% of all PA; less than 150 cases have been reported through the literature to date [14]. Pituitary carcinomas are defined by the wide metastatic spread of the primitive pituitary tumor, mainly in the CNS; The more frequently identified phenotypes are prolactinomas and corticotroph adenomas [14].

“…in the whole population of patients with sporadic and isolated pituitary adenomas, very young patients with macroadenoma may be at higher risk of MEN1 mutations.”

In a recent review, Mete et al. did not clearly mention mutations in the MEN1 gene as a biomarker of aggressiveness in pituitary adenomas [15]. However, the authors stated that loss of chromosome 11p and/or 11q, the region known to harbor the MEN1 locus, could be a critical step in prolactinoma progression to aggressive behavior [15]. Similarly, the histopathological study conducted by Trouillas et al. showed that the PA of patients with MEN1 syndrome were statistically higher in size and more often invasive than in non-MEN1 patients [12]. Despite rarity of both diseases, pituitary carcinomas have recently been described in patients harboring MEN1 syndrome [16,17]. In a large series of patients with DA-resistant prolactinomas, Vroonen et al. also included three patients with pituitary carcinomas and four with locally aggressive tumors (all patients have macroadenomas). MEN1 syndrome was identified respectively in 1/3 (33.3%) and 1/4 (25%) of these patients. One remaining patient, diagnosed with a highly aggressive PA, presented a MEN1-like phenotype but apparently without mutations in MEN1 [18]. Overall, the study included four patients with a mutation in MEN1, suggesting that, in a large series, MEN1 syndrome could account for a significant proportion of pituitary carcinomas or very aggressive PA.

“…MEN1 syndrome is associated with more aggressive pituitary adenomas associated with higher risk of progression/recurrence, which still remains difficult to control.”

Whether or not the MEN1 protein plays a role in the progression of PA remains indisputable. A recent study conducted in a MEN1 mouse model of PA showed that re-expression of the MEN1 gene within pituitary adenoma cells significantly decreases tumor cell proliferation, supporting the role of MEN1 as a tumor suppressor gene [19].

In conclusion, although recent clinical cases reported MEN1-related pituitary carcinomas, there is still no evidence for a higher risk of pituitary carcinoma in MEN1 syndrome compared with the general population (i.e., nonmutated). Undoubtedly, MEN1 syndrome is associated with more aggressive PA associated with higher risk of progression/recurrence, which still remains difficult to control [20].

Given the rarity of both MEN1 syndrome and the occurrence of pituitary carcinoma, a large and international study should be of interest to make light on a possible association between these two pathological conditions.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.