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Updates on the Molecular Profile of Gastrointestinal Stromal Tumors

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 12364

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Special Issue Editors

Dr. Maria Cristina Sini

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Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche (CNR), 07100 Sassari, Italy
Interests: molecular profile of gastrointestinal stromal tumors (GIST); clinical cancer genomic profiling; translational medicine; molecular genetics; cancer; solid tumor; molecular biomarkers; NGS technologies
Special Issues, Collections and Topics in MDPI journals

Dr. Grazia Palomba

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Dear Colleagues,

Gastrointestinal stromal tumors (GIST), although relatively rare, are the most common primary mesenchymal tumors of the gastrointestinal tract. Most GISTs tumors harbor activating mutations in the tyrosine kinase receptor c-KIT and express the tyrosine kinase KIT oncoprotein. Another member of the RTK family, PDGFRα, is associated with the pathogenesis of GIST.

Tumor stage classification and molecular profile are important for tumor diagnosis and indispensable for individualized treatment against malignancies. Genotyping has become an integral part of management of GISTs undergoing tyrosine kinase inhibitor therapy.

In this Special Issue, we focus on novel tumor biomarkers to investigate immunological profiles in gastrointestinal stromal tumors. Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) could define novel gene expression patterns associated with immune checkpoint inhibitors response.

This Special Issue aims to collect original research, short communications, or timely reviews on clinical, pathological, and molecular aspects and alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies.

Dr. Maria Cristina Sini
Dr. Grazia Palomba
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular profile
novel tumor biomarkers
predictive biomarkers for therapeutic outcomes
immunological profile
GIST immune microenvironment
immunotherapy

Published Papers (6 papers)

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Research

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14 pages, 1798 KiB

Open AccessArticle

The Prognostic Value of Plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) in Patients with Gastrointestinal Stromal Tumor

by Charlotte Margareta Brinch, Estrid Hogdall, Niels Junker, Holger Jon Moeller, Birgitte Sandfeld-Paulsen, Pieter de Heer, Luit Penninga, Philip Blach Rossen, Anders Krarup-Hansen and Ninna Aggerholm-Pedersen

Cancers 2022, 14(23), 5753; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235753 - 23 Nov 2022

Cited by 1 | Viewed by 1336

Abstract

Background: This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). Methods: Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. Results: No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. Conclusions: Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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22 pages, 2565 KiB

Open AccessArticle

Characterization of Aberrations in DNA Damage Repair Pathways in Gastrointestinal Stromal Tumors: The Clinicopathologic Relevance of γH2AX and 53BP1 in Correlation with Heterozygous Deletions of CHEK2, BRCA2, and RB1

by Ting-Ting Liu, Chien-Feng Li, Kien-Thiam Tan, Yi-Hua Jan, Pei-Hang Lee, Chih-Hao Huang, Shih-Chen Yu, Cheng-Feng Tsao, Jui-Chu Wang and Hsuan-Ying Huang

Cancers 2022, 14(7), 1787; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071787 - 31 Mar 2022

Cited by 1 | Viewed by 2267

Abstract

Genetic aberrations involving DNA damage repair (DDR) remain underexplored in gastrointestinal stromal tumors (GISTs). We characterized DDR abnormalities using targeted next-generation sequencing and multiplex ligation-dependent probe amplification, and performed immunofluorescence (IF) and immunohistochemistry (IHC) analyses of γH2AX and 53BP1. Consistent with IF-validated nuclear co-localization, γH2AX and 53BP1 showed robust correlations in expression levels, as did both biomarkers between IF and IHC. Without recurrent pathogenic single-nucleotide variants, heterozygous deletions (HetDels) frequently targeted DNA damage-sensing genes, with CHEK2-HetDel being the most prevalent. Despite their chromosomal proximity, BRCA2 and RB1 were occasionally hit by HetDels and were seldom co-deleted. HetDels of CHEK2 and BRCA2 showed a preference for older age groups, while RB1-HetDel predominated in the non-gastric, high-risk, and 53BP1-overexpressing GISTs. Higher risk levels were consistently related to γ-H2AX or 53BP1 overexpression (all p < 0.01) in two validation cohorts, while only 53BP1 overexpression was associated with the deletion of KIT exon 11 (KITex11-del) among genotyped GISTs. Low expressers of dual biomarkers were shown by univariate analysis to have longer disease-free survival (p = 0.031). However, higher risk levels, epithelioid histology, and KITex11-del retained prognostic independence. Conclusively, IHC is a useful surrogate of laborious IF in the combined assessment of 53BP1 and γ-H2AX to identify potential DDR-defective GISTs, which were frequently aberrated by HetDels and a harbinger of progression. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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12 pages, 682 KiB

Open AccessArticle

CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response

by Alexandre de Nonneville, Pascal Finetti, Maelle Picard, Audrey Monneur, Maria Abbondanza Pantaleo, Annalisa Astolfi, Jerzy Ostrowski, Daniel Birnbaum, Emilie Mamessier and François Bertucci

Cancers 2022, 14(5), 1306; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051306 - 03 Mar 2022

Cited by 3 | Viewed by 2226

Abstract

The treatment of gastrointestinal stromal tumors (GIST) must be improved through the development of more reliable prognostic factors and of therapies able to overcome imatinib resistance. The immune system represents an attractive tool. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in sarcomas. CSPG4 expression has never been studied in GIST. We analyzed CSPG4 mRNA expression data of 309 clinical GIST samples profiled using DNA microarrays and searched for correlations with clinicopathological and immune features. CSPG4 expression, higher in tumors than normal digestive tissues, was heterogeneous across tumors. High expression was associated with AFIP low-risk, gastric site, and localized stage, and independently with longer postoperative disease-free survival (DFS) in localized stage. The correlations between CSPG4 expression and immune signatures highlighted a higher anti-tumor immune response in “CSPG4-high” tumors, relying on both the adaptive and innate immune system, in which the boost of NK cells by CSPG4-CAR.CIKs might be instrumental, eventually combined with immune checkpoint inhibitors. In conclusion, high CSPG4 expression in GIST is associated with better DFS and offers an immune environment favorable to a vulnerability to CAR.CIKs. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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Review

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21 pages, 2045 KiB

Open AccessReview

The Crosstalk and Clinical Implications of CircRNAs and Glucose Metabolism in Gastrointestinal Cancers

by Xiaonuan Luo, Yin Peng, Xinmin Fan, Xiaoxun Xie, Zhe Jin and Xiaojing Zhang

Cancers 2023, 15(8), 2229; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082229 - 10 Apr 2023

Viewed by 1478

Abstract

The majority of glucose in tumor cells is converted to lactate despite the presence of sufficient oxygen and functional mitochondria, a phenomenon known as the “Warburg effect” or “aerobic glycolysis”. Aerobic glycolysis supplies large amounts of ATP, raw material for macromolecule synthesis, and also lactate, thereby contributing to cancer progression and immunosuppression. Increased aerobic glycolysis has been identified as a key hallmark of cancer. Circular RNAs (circRNAs) are a type of endogenous single-stranded RNAs characterized by covalently circular structures. Accumulating evidence suggests that circRNAs influence the glycolytic phenotype of various cancers. In gastrointestinal (GI) cancers, circRNAs are related to glucose metabolism by regulating specific glycolysis-associated enzymes and transporters as well as some pivotal signaling pathways. Here, we provide a comprehensive review of glucose-metabolism-associated circRNAs in GI cancers. Furthermore, we also discuss the potential clinical prospects of glycolysis-associated circRNAs as diagnostic and prognostic biomarkers and therapeutic targets in GI cancers. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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21 pages, 1104 KiB

Open AccessReview

Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision

by Mojca Unk, Barbara Jezeršek Novaković and Srdjan Novaković

Cancers 2023, 15(5), 1498; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051498 - 27 Feb 2023

Cited by 4 | Viewed by 1992

Abstract

Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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16 pages, 1061 KiB

Open AccessReview

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

by Maria Cecilia Mathias-Machado, Victor Hugo Fonseca de Jesus, Leandro Jonata de Carvalho Oliveira, Marina Neumann and Renata D’Alpino Peixoto

Cancers 2022, 14(21), 5330; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215330 - 29 Oct 2022

Cited by 11 | Viewed by 2380

Abstract

Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60–70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10–15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes. Full article

(This article belongs to the Special Issue Updates on the Molecular Profile of Gastrointestinal Stromal Tumors)

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