Epigenetic Modifications as Novel Biomarkers for Diagnosis, Prognosis, and Therapeutic Targeting in Thyroid, Pancreas, and Lung Neuroendocrine Tumors

Abstract

Neuroendocrine neoplasms (NENs) comprise a heterogeneous tumor group arising from neuroendocrine cells, commonly originating in the gastroenteropancreatic tract and bronchopulmonary system. Their incidence has risen significantly, owing to improved diagnostic techniques and increased clinical recognition. While previous reviews have explored the molecular and genetic basis of NENs, limited attention has been given to the role of epigenetic modifications, particularly DNA methylation, in tumorigenesis and disease progression. This review focuses on lung, pancreas, and thyroid well-differentiated neuroendocrine tumors (NETs), highlighting epigenetic mechanisms, particularly DNA methylation, as promising biomarkers for early diagnosis and risk stratification. Aberrant DNA methylation can silence key tumor suppressor genes, including RASSF1A and CDKN2A, thereby promoting tumorigenesis. Integrating DNA methylation profiles with conventional biomarkers such as chromogranin A (CgA) may enhance diagnostic accuracy and inform therapeutic strategies. Emerging epigenetic therapies offer potential avenues for personalized treatment based on molecular profiling. Unlike prior reviews that broadly cover genetic and epigenetic changes in NENs, this review uniquely emphasizes the translational potential of epigenetic biomarkers in clinical practice. By synthesizing recent findings and evaluating their clinical implications, we aim to bridge the gap between molecular research and practical applications in diagnosis, prognosis, and therapy.

Keywords: DNA methylation; epigenetic alterations; neuroendocrine neoplasms; well-differentiated neuroendocrine tumors.

Figure 1

Biomarkers in pulmonary, medullary thyroid, and pancreatic neuroendocrine tumors. For pulmonary neuroendocrine tumors, biomarkers such as Chromogranin A, Synaptophysin, CD56, and Antigen Kiel 67 (Ki-67 or MiB1) are highlighted as important tumor presence and proliferation indicators. In medullary thyroid carcinoma (MTC), biomarkers including Calcitonin, Carcinoembryonic Antigen (CEA), circulating free DNA (cfDNA) fragmentation, and genetic mutations such as REarranged during Transfection (RET) and rat sarcoma (RAS) are essential for diagnosis and prognosis. Additionally, epigenetic markers like O6-methylguanine-DNA methyltransferase (MGMT) gene hypermethylation, cyclin-dependent kinase inhibitor 2A (CDKN2A or p16INK4a), Ras Association Domain Family Member 1 (RASSF1A), and SRY-related HMG-box 17 (SOX17) are shown to play significant roles. In pancreatic neuroendocrine tumors, chromogranin A (CgA), Neuron-Specific Enolase (NSE), Claudin-18, Ki-67 (MiB1), and genetic alterations such as Multiple Endocrine Neoplasia, Type 1 (MEN1) mutation, Death Domain Associated Protein (DAXX), and alpha-thalassemia mental retardation X-linked (ATRX) mutations, and methylation of genes like tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and MutL Homolog 1 (MLH1) are presented as critical biomarkers. The figure also includes the role of somatostatin receptors (SSTRs) in all three tumor types, further contributing to tumor diagnostics and therapeutic targeting.

Figure 2

Epigenetic modifications in gene regulation. The chromatin structure, consisting of DNA wrapped around histone proteins to form nucleosomes, is depicted. DNA methylation is shown as the addition of methyl groups to cytosine bases (5-methylcytosine) within the cytosine–guanine (CpG) dinucleotides or CpG islands, with methylated (5mC) and unmethylated cytosine bases (C) marked. Histone modifications, such as methylation and acetylation of the histone tails, are represented as chemical marks that alter chromatin structure and influence gene accessibility. These modifications can either condense the chromatin, repressing transcription, or relax the chromatin, facilitating transcription. Transcription factors initiate the process of transcription, where messenger RNA (mRNA) is synthesized from the DNA template, enabling gene regulation expression by these epigenetic marks.