Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis

Melone, Viola; Salvati, Annamaria; Palumbo, Domenico; Giurato, Giorgio; Nassa, Giovanni; Rizzo, Francesca; Palo, Luigi; Giordano, Alessandro M.; Incoronato, Mariarosaria; Vitale, Mario; Mian, Caterina; Biase, Immacolata Di; Cristiano, Stefano; Narciso, Viviana; Cantile, Monica; Mauro, Annabella Di; Tatangelo, Fabiana; Tafuto, Salvatore; Modica, Roberta; Pivonello, Claudia; Salvatore, Marco; Colao, Annamaria; Weisz, Alessandro; Tarallo, Roberta

doi:10.1186/s12967-022-03511-7

Cited by 17 publications

(15 citation statements)

References 98 publications

(91 reference statements)

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“…Consequently, the presence of genetic variations that are vulnerable to potential individualized therapies are definitely relevant, especially for patients with high grade GI‐NENs. Melone et al showed ATM‐dependent signaling was the most significant pathways in NEN patients of thyroid, pancreas, intestine, and lung by multi‐omics analysis 41 . In our study, BRAC1/2 and ATM alterations of ATM‐dependent signaling were found in GI‐NENs also.…”

Section: Discussionsupporting

confidence: 71%

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Genetic alterations of GI‐NECs involving three main signaling pathways

et al. 2023

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Background Gastrointestinal (GI)‐neuroendocrine neoplasms (NENs) are subclassified in neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). The genetic characteristics of GI‐NEN has been a hot issue in recent years, but more studies are needed to provide further details. This study aims to provide additional data about genomic characteristics of GI‐NENs and the genetic differences between NETs and NECs. Patients and Methods Thirteen samples were selected for next‐generation sequencing (NGS) analysis with a 425‐gene panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were calculated as well as immunohistochemistry (IHC) was used to test for protein expression. Results Genetic alterations were very common in NECs, but rare in NETs. The average TMB of NETs and NECs was 2.3 and 6.9, respectively. The TMB of NECs was significantly higher compared to NETs. The TP53 mutation rate was significantly higher in NECs than in NETs (100% vs. 20%), other mutations involved MTOR (n = 2, 15.4%), DDR2 (n = 3, 23.1%), ERBB4 (n = 1, 7.7%), BRCA1 (n = 1, 7.7%), BRCA2 (n = 1, 7.7%), ATM (n = 1, 7.7%), and SMAD4 (n = 1, 7.7%). Deep loss of SMAD4 (1/3, 33.3%), SDHB (1/3, 33.3%), RB1 (1/3, 33.3%), and BRCA2 (1/3, 33.3%), high‐level amplification of CRKL (1/3, 33.3%), CCNE1(1/3, 33.3%), and MCL1(1/3, 33.3%) were found in NECs. The integrated analysis found these genetic alterations frequently involve DNA repair and cell cycle, PI3K/AKT/mTOR and TGF‐β/SMAD4 signaling pathways. Conclusion Genetic alterations were very common in NECs and rare in NETs, and frequently involved three main signaling pathways. NEC patients harboring these genetic alterations may benefit from targeted therapy and PD‐1/PD‐L1 immunotherapy.

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Section: Discussionsupporting

confidence: 71%

“…Melone et al showed ATM-dependent signaling was the most significant pathways in NEN patients of thyroid, pancreas, intestine, and lung by multi-omics analysis. 41 In our study, BRAC1/2 and ATM alterations of ATM-dependent signaling were found in GI-NENs also.…”

Section: F I G U R Esupporting

confidence: 68%

Genetic alterations of GI‐NECs involving three main signaling pathways

et al. 2023

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“…Recently, the overexpression of 13 selected circulating miRNAs has been described in NENs and medullar, in comparison to healthy subjects. It was the first study in which a set of circulating miRNAs was identified that could represent a tumor signature for NEN diagnostics [ 107 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating Neuroendocrine Tumor Biomarkers: Past, Present and Future

Komarnicki

Musiałkiewicz

Stańska

et al. 2022

JCM

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Neuroendocrine tumors are a heterogeneous group of neoplasms originating from the diffuse endocrine system. Depending on primary location and hormonal status, they range in terms of clinical presentation, prognosis and treatment. Functional tumors often develop symptoms indicating an excess of hormones produced by the neoplasm (exempli gratia insulinoma, glucagonoma and VIPoma) and can be diagnosed using monoanalytes. For non-functional tumors (inactive or producing insignificant amounts of hormones), universal biomarkers have not been established. The matter remains an important unmet need in the field of neuroendocrine tumors. Substances researched over the years, such as chromogranin A and neuron-specific enolase, lack the desired sensitivity and specificity. In recent years, the potential use of Circulating Tumor Cells or multianalytes such as a circulating microRNA and NETest have been widely discussed. They offer superior diagnostic parameters in comparison to traditional biomarkers and depict disease status in a more comprehensive way. Despite a lot of promise, no international standards have yet been developed regarding their routine use and clinical application. In this literature review, we describe the analytes used over the years and cover novel biomarkers that could find a use in the future. We discuss their pros and cons while showcasing recent advances in the field of neuroendocrine tumor biomarkers.

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“…Total RNA–seq procedure was performed as described previously [ 21 , 22 ]. Briefly, before use, total RNAs concentration, from three biological replicates of DLD1-pEGFP and DLD1-pEGFP_hRIZ2 cells, was measured using RNA HS kit on a Qubit fluorimeter (Life Technologies, Monza, Italy) while its quality and integrity assessed with the Agilent 4200 TapeStation System (Agilent Technologies, Milan, Italy).…”

Section: Methodsmentioning

confidence: 99%

RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer

Di Donato,

Di Zazzo,

Salvati

et al. 2023

J Transl Med

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Background Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. Methods We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. Results Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. Conclusions Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism.

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Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis

Cited by 17 publications

References 98 publications

Genetic alterations of GI‐NECs involving three main signaling pathways

Genetic alterations of GI‐NECs involving three main signaling pathways

Circulating Neuroendocrine Tumor Biomarkers: Past, Present and Future

RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer

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