The MEN1 gene is located on chromosome 11q13, which is mutated in patients with an inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN-1) [3]. The protein menin coding by MEN1 regulates transcription, chromatin structure, genome stability, and cellular proliferation through direct association with interacting protein partners, or via the modulation of key cellular signaling pathways [4]. MEN1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumors, mimicking human MEN1 syndrome, indicating that MEN1 as a tumor suppressor gene in endocrine tumors [11]. Recently, several reports have demonstrated that menin protein is associated with development of non-endocrine tumors. For instance, menin has been shown to associate with trxG family proteins in a histone methyltransferase complex, and it is required for maintenance of Hox family gene expression, and initiation of MLL-mediated leukemogenesis and myeloid transformation [12, 13].
In our study, 1.81% MEN-1 cases were identified with breast cancer, which is significantly higher than the incidence of breast cancer in general population (The 10-year prevalence varies from 134 to 367 per 100,000 across different Chinese regions) [14]. Several researchers have found that silencing of the MEN1 gene results in proliferative gene expression changes in primary mammary luminal progenitor cells in human breast tissue [15]. Romain T et al by analyzing the expression of menin in 354 human breast cancers, found that a lower expression was associated with ER-negative breast cancer (P = 0.041) [16]. Rachel S et al also found that the increased breast cancer risk in MEN-1 carriers was not related to other known breast cancer risk factors or familial cancer history, and with earlier age of onset (45 vs 57.5 years old) [17]. However, in our study, the onset age of breast cancer ranged from 42 to 71(average 53) years old no earlier than mean age at diagnosis of breast cancer in Chinese which is 49 yrs[14]. Whatever, there has been plenty evidence suggested intimate connection between MEN-1 and breast cancer, and significance of breast cancer screening in MEN-1 female patients from the age of 40 years. In our study, one patient diagnosed with breast cancer and prolactinoma. In animal experiment, prolactin was confirmed to play the role as a cancer initiator and promoter [18]. However, recent study found that the relative risk of breast cancer in 1,342 patients with treated hyperprolactinemia was 1.07, which didn’t suggest increased breast cancer risk [19].
We found that MEN-1 complicated with thyroid papillary carcinoma is not uncommon, with an incidence of 4.52% in our study higher than the incidence of PTC in the general population (0.5–6.9/100,000) in China [20]. However, the current view was that the association of thyroid abnormalities in patients with MEN1 may be incidental [3]. Genetic analysis of papillary cancer tissue did not show LOH in MEN-1 patients, and there were no evidence in vitro, animal or human studies associating germline mutations of MEN1 with the development of PTC [21]. Although there was insufficient evidence for an association between MEN-1 and the development of thyroid cancer, we speculated that the following factors might contribute to the higher incidence of PTC in MEN-1 patients. There were two cases of PTC with pituitary growth hormone adenoma which is a risk factor for occurrence of PTC [22]. Furthermore, thyroid ultrasound before surgery of hyperparathyroidism was needed in our center, which may increase the detection rate of thyroid cancer which is asymptomatic, low-malignant, slow-growing tumor, and often overlooked. MEN1 patients need to frequent perform radioactive examinations such as CT and nuclear medical examination to evaluate tumors, resulting in thyroid exposure to excessive radiation which may also be a risk factor for the increased incidence of thyroid cancer.
Three MEN-1 cases presented urologic neoplasms including renal clear cell carcinoma (RCC), renal papillary cell carcinoma and upper tract urothelial carcinoma(UTUC). Perakakis reported a German family with MEN-1 also have been diagnosed with atypical tumor including renal cell carcinoma, papillary thyroid cancer and prostate cancer [23]. However, no studies have confirmed that the mutation of MEN1 gene is associated with the development of urinary tumors. We supposed that such a high incidence of urologic neoplasms observed in MEN-1 patients may be related to urolithiasis caused by early hyperparathyroidism. A prospective study by Jeroen A found that an early kidney stone diagnosis (≤ 40 years) was associated with an increased RCC (HR: 3.08, 95% CI 1.55–6.11) and UTUC (HR: 1.66, 95% CI 1.03–2.68) risk [24]. However, the pathophysiological mechanisms that may underlie the development of renal cell carcinoma and urothelial cancer in patients with urolithiasis remain unexplored.
Regarding the other atypical tumor entities (brain glioma, cervical cancer, lung cancer) found in MEN-1 patients in this study were few relevant reports. Menin represses PTN transcription through Polycomb gene-mediated trimethylation of H3K27 which is associated with lung adenocarcinoma. Menin is expressed not only in endocrine tumors but also in many non-endocrine human cancer cells, such as in breast, cervical, brain glioma and gastric cancer cell lines [25], which may suggest potential correlation between MEN-1 and these non-endocrine tumors. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis.
There were two patients diagnosed with co-occurrence of primary hepatic carcinoma (PCC) and MEN-1. But both of them suffered from Hepatitis B which should be major risk factor for PCC. Actually, heterozygous ablation of MEN-1 in female mice reduces chemical carcinogen-induced liver carcinogenesis and represses the activation of the inflammation pathway.[26]
In addition, the clinical characteristics of MEN-1 patients with and without other malignancies were compared in our study. There was no significant difference in onset age between the two groups. However, the prevalence of PitNET, GEP-NET, carcinoid, and adrenal adenoma were higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignances. Although characteristics of MEN-1 gene mutations were not compared between these two groups, we speculated that loss of function from menin protein may be more severe in MEN-1 patients with malignant tumors according to more serious clinical features.
Germline activating mutations of RET caused MEN-2, whose variations in expression also have been discovered in several different solid tumor types including PTC, non-small cell lung cancer, breast cancer, pancreatic cancer and so on [10]. In our study, a concurrent diagnosis of PTC was found in MEN-2 patients. Integrated multiplatform analyses performed through The Cancer Genome Atlas (TCGA) network yielded RET fusions in 6.8% of PTC samples [27]. Other studies have shown somatic RET locus rearrangements at chromosome 10q11.2 presenting in 2.5–73% of sporadic PTC and 22–87% of post-Chernobyl PTC, occurring more frequently in childhood than adulthood thyroid cancer. The other case reported in this study is co-occurrence of MEN-2 and multiple myeloma, but we didn’t find any other case report or relevant in vitro and in vivo studies.
It is a study summarized the largest number of patients who were diagnosed concurrently of MEN-1 or MEN-2 with malignant tumors which not belong to MEN in single center. In our study, high prevalence of breast cancer, PTC and urologic neoplasms were found in MEN-1 patients. Meanwhile, the occurrence of other malignant tumors such as brain glioma, squamous cell lung carcinoma, primary hepatic carcinoma, cervical cancer and multiple myeloma was also found, which was seldom reported in the past. Since the role of MEN-1 and RET as a tumor regulator in many organs remains to be established, it is difficult to distinguish whether it is random observations or etiological relations to MEN-1 and MEN-2. However, more severe clinical features (higher prevalence of endocrine neoplasm) found in MEN-1 patients with other malignant tumors comparing to without malignant tumors may suggest more serious loss of function from menin protein. It is a limitation that we did not obtain all gene mutation results of MEN patients to further analyze the possible underlying mechanisms of malignancies occurred in MEN-1 patients. The evidence that MEN-2 patients are more prone to malignancy is weak because the number of cases is too small to rule out the possibility of chance occurrence