Endocrine Abstracts

Introduction: Gastric neuroendocrine tumors (GNET) are rare gastric neoplasms which are developed due to hypergastrinemia and enterochromaffin-like (ECL) cell hyperplasia. Although the effect of the circadian clock system disruption on tumorigenesis has been already studied in various malignancies and autoimmune diseases, the role of the peripheral clock system in the transition from ECL-cell hyperplasia to GNEN1 (Type 1 Gastric Neuroendocrine Neoplasms) remains unexplored.

Aim: We aimed to investigate the expression of clock-related genes in peripheral blood mononuclear cells (PBMCs) and gastric tissues of the same patients with ECL-cell hyperplasia and patients with GNEN1.

Methods: Fresh frozen gastric tissues were collected between (9:00 -11:00 am) from 9 patients diagnosed with GNEN1. The histological reports confirmed the presence of ECL and GNEN1 lesions (in each separate specimen) collected from the same patient. PBMCs were also isolated from the whole blood (8:00-9:00am) of the same patients and 10 patients with confirmed ECL-cell hyperplasia. CLOCK, BMAL1, CRY1, PER2, REV-Erb, ROR-α, GR-α genes expression was evaluated by qPCR in PBMCs, ECL-cell hyperplastic and its paired GNEN1 lesions. Clinical, histological and epidemiological data of patients were also collected.

Results: The mean age of patients was 57.8±12.8 years old. Paired analysis revealed that the expression of BMAL-1 and CLOCK was significantly (P<0.01) increased while the expression of REV-Erb and GR-α was reduced (P<0.05) in GNE1 tissue as compared to adjacent ECL tissue. There was no significant difference in the expression of PER-2 and CRY-1 in GNE1 tissues as compared to adjacent ECL tissues. Interestingly, the expression of CLOCK, PER2 and REV-Erb was significantly increased in PBMCs of GNE1 as compared to patients with ECL-cell hyperplasia.

Conclusion: Our data indicate for the first time that there is aberrant circadian clock gene expression in human gastric neuroendocrine tumors in both gastric lesions and PBMCs. Since CLOCK gene was overexpressed, apart from GNEN1 lesions, in PBMCs of patients with GNEN1 as compared to PBMCs isolated from subject diagnosed with ECL-cell hyperplasia, its potential role as an non-invasive biomarker of transition of ECL-cell hyperplasia to non-invasive GNEN1 could be explored. However, a larger sample size of patients is necessary to evaluate the role of dysregulation of the local circadian clock system in the development and/or evolution of these neoplasms.