In the study of pancreatic NEC, mutations of P53 and RB genes were found to be very common, while smad4/Dpc4, DAXX and ATRX1 remained unchanged. In contrast, in 45% of NET, DAXX and ATRX1 were absent, while P53 and RB remained unchanged. The overexpression of BCL2 was also mainly found in NEC and related to the proliferation activity, while NET was more related to the loss of heterozygosities of MEN-1 and11q. These studies suggested that small cell carcinoma and large cell carcinoma have similar genetic change characteristics, and there is a great difference between them and well-differentiated NET. Therefore, in the study of NET and NEC, it is believed that the two are not continuous processes in the disease spectrum, but two different types of diseases with different molecular biological mechanisms [6, 7].
In our study, the main component of NEN in this patient’s pancreas was NET G2, in which 4 foci (0.1~0.2cm) of advanced neuroendocrine tumors (NEN G3) appeared, and it was difficult to differentiate NET G3 from NEC morphologically. Immunohistochemistry showed that P53 gene was mutated in the NEN G3 region and RB1 gene was not absent. In addition, the morphologic features of liver metastases were all high-grade neuroendocrine tumors, and the immunohistochemical expression was consistent with that of NEN G3 in the pancreas. Therefore, it should be diagnosed that the presence of NEC in the pancreas NET G2 and with NEC liver metastasis. However, according to the current theory, NET and NEC have different molecular biological mechanisms. So, this diagnosis was still in doubt. Whether NET and NEC shared a common pathogenesis remained to be discussed. To further analyze the relationship between the two types, we performed whole exon sequencing on the corresponding paraffin tissues of primary pancreas NET G2 (Ki67 10%) and liver metastasis NEN G3 (Ki67 70%). Thirteen individual cell mutations were found in pancreas NET G2 and 72 in liver NEN G3. Bioinformatics analysis revealed that P.S493N point mutation of TRIOBP gene was detected in both primary NET and metastatic foci (NEN G3).
The TRIOBP gene encodes multiple proteins, which together play crucial roles in modulating the assembly of the actin cytoskeleton. TRIOBP-1 (also known as TARA or TAP68) is a mainly structured protein that is ubiquitously expressed and binds to F-actin, preventing its depolymerization. It has been shown to be important for many processes including in the cell cycle, adhesion junctions, and neuronal differentiation. Few studies have been conducted on the correlation between TRIOBP gene and tumors. At present, no studies have been conducted on the correlation between TRIOBP gene and the NENs. This study suggests that TRIOBP gene may be involved in the occurrence and development of the NENs.
At the same time, the MDM4 oncogene in liver metastases was amplified 5 times. The human MDM4 gene is in chromosome 1q32 and consists of 10 introns and 11 exons. The relative molecular weight of the protein product is 54864 [8]. The human full length MDM4 consists of 490 amino acids, and contains 3 conserved domains: P53-binding domain and Zn finger domain at N terminal, RING finger domain at C terminal. It also contains a rich cid residue structure domain (acidic domain). When MDM4 is phosphorylated, its P53-binding domain can bind to the transcriptional activation domain of wild-type and mutated proteins to form the MDM4/P53 complex and inhibit the transcriptional activity of P53 [9, 10]. As a crucial regulatory factor in the upstream of p53, MDM4 plays an important role in normal tissue growth and tumor development. MDM4, as an oncogene, was less activated in the reproductive peak age, but increased rapidly with age. The functions of MDM4 splices, such as their significance in the process of tumor genesis and development and its role in the development of chemotherapy resistance, will be the focus of future research. In this case, MDM4 was significantly amplified in high-grade NEN compared with NET in the pancreas. Is it suggested that MDM4 is similar to P53 gene? If the obvious amplification represents a higher degree of malignancy, this will be one of the focuses of our next research. In the future, whether MDM4 inhibitor provide a new option for NEN treatment, or whether they will be more effective for NEC treatment of P53 mutation.