Researchers have discovered a set of frequently mutated genes in neuroendocrine neoplasms (NENs), such as medullary thyroid carcinoma (MTC), that could serve as diagnostic and prognostic markers. Furthermore, the signaling pathways dependent on these genes could become a potential therapeutic target in the future, according to a recently published study in the Journal of Translational Medicine.

The incidence of NENs has significantly increased over the last 4 decades. Unfortunately, because of their unspecific symptomatology and indolent growth, many cases are metastatic at the moment of diagnosis, making it difficult to identify the primary site. There are currently scarce biological markers for an early diagnosis.

To address this issue, the authors aimed to detect new molecular markers with potential clinical applications in both the diagnosis and management of NENs. The study comprised 46 tumor biopsies of different NENs, including MTC and gastroenteropancreatic NENs (GEP-NENs). Researchers also obtained isolated ARN from 20 different MTCs. 

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After performing nucleic acid extraction from the tumor samples, the authors prepared libraries of mutational, transcriptional, and small-RNA profiling to apply a multiomics approach, which allowed the identification of common molecular signatures among the different NENs included in the study.

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After analysis, the authors noted that most of the genes with more sequence variations were involved in the DNA damage response pathway. The mediator of DNA damage checkpoint protein 1 (MDC1) was the most mutated gene, and others involved in DNA repairs, such as ATM and BRCA1, were also among the list of 20 top mutated genes.

Using small-DNA profiling, researchers identified over 600 microRNAs frequently expressed in both GEP-NENs and MTC. 

The authors also assed the plasma of 3 patients with NEN and detected many of the microRNAs previously identified in tumor samples, further supporting their value as potential biomarkers. Some of these microRNAs even appear to appear in different levels of tumor differentiation which could give them a potential use in both diagnosis and prognosis.

Many of the messenger ARN targets of the identified micro ARNs were associated with the ATM gene found amongst the most mutated genes of the samples, suggesting that ATM signaling could eventually become a therapeutic target.

“Further experimental and preclinical evidences are needed by establishing in vitro and in vivo models demonstrating their effectiveness and potential clinical application in NENs,” the authors concluded.


Melone V, Salvati A, Palumbo D, et al. Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis. J Transl Med. Published online July 6, 2022. doi:10.1186/s12967-022-03511-7