Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a global prevalence ranging from 1 to 10 per 100,000 individuals, with geographical incidence variations that may reflect the founder effect [9]. Despite its global presence, data on MEN1's prevalence in Colombia remains sparse. Our 12-year study documents the clinical trajectory of a Colombian family carrying a novel MEN1 germline variant: c.698dup. Notably, with 10% of MEN1 variant arising de novo [3], the origin of the variant in this family—whether inherited from individual I-1, who had gastric cancer or as a new variant in individual II-4—is uncertain (Fig. 1a). The absence of this variant in existing databases and the lack of a Colombian MEN1 registry complicate the assessment of a potential founder effect, highlighting the need for comprehensive case tracking.
The MEN: c.698dup variant was initially detected in the index case upon the emergence of clinical symptoms. A follow-up cascade genetic screening was performed on eight high-risk family members, uncovering four more carriers of this variant. Given that MEN1 predominantly manifests through tumors in the parathyroid glands, anterior pituitary, and gastroenteropancreatic (GEP) axis, alongside possible tumors in other regions like the adrenocortical glands, lungs, and thymus [3], the early identification of this variant holds substantial value. The age-associated risk of MEN1 reveals that over 50% of individuals show clinical features by the age of 20 years and a staggering 95% by age 40 years.
PHPT is the most common initial presentation in MEN1, occurring in about 85% of patients, and often serves as the first sign of this disorder [10]. In the family we studied, everyone who clinically manifested the disease (III-2, II-4, III-3, and III-4) initially presented with PHPT, accompanied by varying degrees of hypercalcemia.
Pancreatic neuroendocrine tumors (pNETs) are common in MEN1, with a 40% incidence rate, typically as non-functional pancreatic neuroendocrine tumors (NF-pNETs). Contrary to this trend, our study documents two cases of functional NETs within the same family. The index patient was diagnosed with an insulinoma at 24 and developed an ACTH-producing pancreatic neuroendocrine carcinoma (NEC) at 29—patient II-4 presented with Zollinger-Ellison syndrome at 48 [11]. Meanwhile, patients III-3, III-4, and IV-1, aged 31, 24, and 14, respectively, remain asymptomatic under close clinical surveillance.
Insulinomas are the most common functional NETs, representing 7–31% of cases, with gastrinomas accounting for 5% [12]. These findings align with the presentations in the index case and patient II-4. Notably, the index case's second pancreatic tumor, causing ectopic ACTH secretion syndrome (EAS), is a novel finding in MEN1, as such carcinomas are typically associated with thymic NETs [13–17]. This is the first report of a family exhibiting an ACTH-producing pancreatic NEC, marking a distinctive finding within the landscape of MEN1 phenotypic expression.
The 2022 WHO classification differentiates neuroendocrine neoplasms into well-differentiated NETs and poorly differentiated NECs [18]. NETs are graded as G1, G2, or G3 based on mitotic rate and Ki-67 index, reflecting their proliferative activity. NECs, characterized by high-grade nuclear features, display a high mitotic count (often > 20 per 2 mm2) and Ki-67 index (typically > 55%) and are associated with aggressive clinical behavior and poor prognosis [18, 19].
NECs are further classified into small cell (SCNECs) or large cell types (LCNECs), rarely linked to hormonal syndromes or somatostatin receptor expression. The case in question involves a functional ACTH-producing P-SCNEC, a rare entity in MEN1, adding to the spectrum of MEN1-NET phenotypic diversity.
The heterogeneity of pNETs encompasses variations in histopathological grade, hormone secretion, and genetic alterations. Notably, grade progression is more common in metachronous than synchronous metastases [20]. Current studies based on next-generation sequencing (NGS) interpretation have shown that tumor variant burden (TMB) in synchronous and metachronous metastatic samples (liver and lymph nodes) is sometimes different from that of the primary tumor (pancreas). Analysis of the clonal and subclonal architecture and genetic profile suggests that most metastatic subclones could be traced back to the initial tumor [21, 22].
PitNETs, or pituitary adenomas, are among the three primary tumors associated with MEN1, with a 30–50% prevalence in affected individuals [23]. Typically developing between the fourth and sixth decades of life, PitNETs are rare before age 20. Prolactinomas are the most common type of PitNET in MEN1, comprising 65% of cases, with somatotropinomas also being significant [24]. This pattern is reflected in the family described in our study. While PitNETs in MEN1 are predominantly macroadenomas (85%), with microadenomas less common (14%) [25], two family members (III-3 and III-4) in our report presented with microadenomas, primarily as prolactinomas, and in one case, with additional GH secretion, which is noted in 5% of PitNETs.
The occurrence of microadenomas in both cases is notable, deviating from the typical macroadenoma presentation in MEN1 [25]. This may be attributed to the early detection of PitNETs in these variant carriers, facilitated by proactive screening, rather than the emergence of clinical symptoms.
This family report exemplifies the clinical heterogeneity of MEN1 syndrome, yet a definitive genotype-phenotype correlation remains elusive. MEN1 is associated with a diverse range of over 20 endocrine and non-endocrine tumors, all linked to loss of heterozygosity (LOH) at chromosome 11q13, where the MEN1 gene resides. We report a new MEN1 germline variant: c.698dup, p.Met233IlefsTer4. The MEN1 gene product, menin, is a tumor suppressor protein with broad expression and four domains: the N-terminal, the middle Thumb, the Palm, and the C-terminal domains. The Thumb and Palm domains contain tetracopeptide repeats crucial for menin protein interactions (Fig. 2a) [26]. These interactions allow menin to regulate gene expression, cell cycle, DNA repair, and other molecular functions [27–29], highlighting its central role in cellular homeostasis.
We propose two molecular mechanisms to explain the pathogenicity of the novel MEN1 variant c.698dup, p.Met233IlefsTer4. The first mechanism concerns the variant's location, which likely causes a methionine-to-isoleucine substitution at position 233 and introduces a premature stop codon shortly after that. This change is expected to result in the loss of the critical palm and fingers domains of menin, disrupting its interaction with menin interaction proteins (MIPs) (Fig. 2b, 2c) [1]. These domains are pivotal for menin's role in various cancer-related pathways, which may contribute to MEN1 phenotype variations in this family. For instance, compromised interaction with FANCD2 could impair DNA repair via the Fanconi anemia pathway [30], while disrupted interaction with MLL1 has been associated with parathyroid adenomas [31]. Altered interactions with proteins such as JunD may affect their oncogenic or tumor-suppressing activities, potentially leading to gastrinomas [27, 32]. Additionally, the menin-PRMT5 interaction is crucial for pancreatic cell proliferation, and its disruption is linked to pancreatic neuroendocrine neoplasms (pNENs). In contrast, the loss of interaction with CHES1 is involved in aggressive pNETs [33, 34]. The menin-NF-kβ interaction also plays a role in suppressing hepatocellular tumors [35].
The second mechanism involves the complete loss of menin protein due to nonsense-mediated decay (NMD), a cellular process that degrades mRNA transcripts with premature stop codons (Fig. 2d) [36–38]. Truncated menin proteins are often undetectable in MEN1 patients, indicating that variants like c.698dup are likely targets for NMD [39]. While further functional studies are needed to confirm these mechanisms, the familial segregation and clinical manifestations provide strong evidence of this variant's pathogenicity.
A deeper understanding of the genetic and molecular consequences of MEN1 variants is essential for developing targeted treatments. For example, functional studies have shown that null menin variants disrupt the interaction with BRCA2, a necessary protein in DNA repair, suggesting that poly (ADP-ribose) polymerase (PARP) inhibitors could be a promising treatment for MEN1-related conditions [40].
Documenting novel MEN1 variants is pivotal for dissecting the diverse phenotypic spectrum associated with this syndrome. Investigating the precise molecular disruptions these variants induce enhances our comprehension of MEN1's pathogenic mechanisms. Such insights enrich our scientific understanding and pave the way for personalized therapeutic interventions that are attuned to the distinct genetic underpinnings of each patient's condition.