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Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors
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Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 18454

Special Issue Editors

Prof. Dr. Emanuela Scarpi

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Guest Editor
Unit of Biostatistics and Clinical Trials, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: biostatistics; clinical trials; observational study; tumor epidemiology; oncology; palliative care; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Paola Ulivi

E-Mail Website
Guest Editor
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” (IRST), via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; biomarkers; liquid biopsy; oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Passardi

E-Mail Website
Guest Editor
Department of Medical Oncology, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; angiogenesis; colorectal cancer; pancreatic cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent years have seen remarkable advances in the treatment of all gastrointestinal cancers. Translational research has led to significant benefits in screening and patient management, and precision medicine is fast becoming the aim of scientific research.

Individualized treatment for gastrointestinal tumors in both adjuvant and metastatic settings is increasingly emphasized. In particular, the introduction of molecular-targeted agents has significantly improved patient outcome, but predictive markers of efficacy, especially for angiogenesis inhibition, are still lacking. Furthermore, immunotherapy has recently been implemented into clinical practice. Due to these new therapeutic options, physicians are confronted with new challenges, such as monitoring progression and stratifying patients for appropriate treatments.

The role of genetic alterations in cancer is well established. It is generally accepted, however, that genetic changes alone do not fully account for malignancy. Growing evidence has indeed implicated the involvement of epigenetic alterations in cancer. Unlike irreversible genetic mutations, epigenetic alterations are potentially reversible, which makes epigenetic therapy (modulation of epigenetic states) an appealing strategy for cancer treatment. Alterations of epigenetic marks could also serve as biomarkers for diagnosis, prognosis, and responses to therapies.

Some of the molecular drivers of inflammation have been repeatedly demonstrated to influence cell death, growth, and metabolic pathways of a pre-cancer or cancer cell. The challenge is to understand how these molecular drivers differ from their function in normal cells and in homeostatic regulation. If key molecular drivers of inflammation for cancer can be identified, novel therapies can be obtained to selectively target their abnormal function in the “inflammatory phase” prior to pre-cancer or cancer cells.

A new approach to biomarker detection is the use of liquid biopsy. Free circulating tumor DNA (fctDNA) can be monitored quantitatively and qualitatively for diagnostic, prognostic, or predictive purposes. Liquid biopsy has the potential to replace tumor tissue analysis in clinical practice and could be used to monitor the extent of tumor burden and to detect tumor heterogeneity and molecular resistance to therapy.

Prof. Dr. Emanuela Scarpi
Dr. Paola Ulivi
Dr. Alessandro Passardi
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • gastrointestinal tumors (esophagus, stomach, colon-rectum, anus, epatobiliary, pancreas)
  • predictive biomarkers of response and toxicity in the adjuvant and metastatic settings
  • genetic and epigenetic markers
  • immunotherapy
  • prognostic biomarkers
  • angiogenesis
  • EGFR and HER2 pathways
  • tumor biopsies
  • circulating tumor cells
  • tumor heterogeneity
  • early diagnosis
  • screening
  • liquid biopsy
  • molecular pathology
  • tumor biology

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Published Papers (7 papers)

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Editorial

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2 pages, 163 KiB  
Editorial
Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors
by Alessandro Passardi, Emanuela Scarpi and Paola Ulivi
Int. J. Mol. Sci. 2023, 24(18), 14283; https://doi.org/10.3390/ijms241814283 - 19 Sep 2023
Cited by 1 | Viewed by 723
Abstract
Gastrointestinal cancers (GC) account for 26% of all cancer incidences and 35% of all cancer-related deaths [...] Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)

Research

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19 pages, 29193 KiB  
Article
MSI-H Detection by ddPCR in Endoscopic Ultrasound Fine Needle Biopsy (EUS-FNB) from Pancreatic Ductal Adenocarcinoma
by Maria Assunta Piano, Elisa Boldrin, Lidia Moserle, Nicoletta Salerno, Dalila Fanelli, Giulia Peserico, Maria Raffaella Biasin, Giovanna Magni, Veronica Varano, Giorgia Zalgelli, Vasileios Mourmouras, Antonio Rosato, Antonio Scapinello, Alberto Fantin and Matteo Curtarello
Int. J. Mol. Sci. 2024, 25(20), 11090; https://doi.org/10.3390/ijms252011090 - 15 Oct 2024
Viewed by 1419
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited survival. Curative opportunities are only available for patients with resectable cancer. Palliative chemotherapy is the current standard of care for unresectable tumors. Numerous efforts have been made to investigate new therapeutic strategies [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited survival. Curative opportunities are only available for patients with resectable cancer. Palliative chemotherapy is the current standard of care for unresectable tumors. Numerous efforts have been made to investigate new therapeutic strategies for PDAC. Immunotherapy has been found to be effective in treating tumors with high microsatellite instability (MSI-H), including PDAC. The ability of the Endoscopic Ultrasound Fine Needle Biopsy (EUS-FNB) to reliably collect tissue could enhance new personalized treatment by permitting genomic alterations analysis. The aim of this study was to investigate the feasibility of obtaining adequate DNA for molecular analysis from EUS-FNB formalin-fixed-paraffin-embedded (FFPE) specimens. For this purpose, FFPE-DNA obtained from 43 PDAC archival samples was evaluated to verify adequacy in terms of quantity and quality and was tested to evaluate MSI-H status by droplet digital PCR (ddPCR). All samples were suitable for ddPCR analysis. Unlike the 1–2% MSI-H frequency found with traditional techniques, ddPCR detected this phenotype in 16.28% of cases. This study suggests the ddPCR ability to identify MSI-H phenotype, with the possibility of improving the selection of patients who may benefit from immunotherapy and who would be excluded by performing traditional diagnostic methods. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
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12 pages, 1680 KiB  
Article
Prognostic Significance of GPR55 mRNA Expression in Colon Cancer
by Hager Tarek H. Ismail, Manar AbdelMageed, Gudrun Lindmark, Marie-Louise Hammarström, Sten Hammarström and Basel Sitohy
Int. J. Mol. Sci. 2022, 23(9), 4556; https://doi.org/10.3390/ijms23094556 - 20 Apr 2022
Cited by 4 | Viewed by 2175
Abstract
G protein-coupled receptor 55 (GPR55) probably plays a role in innate immunity and tumor immunosurveillance through its effect on immune cells, such as T cells and NK cells. In this study, the prognostic value of GPR55 in colon cancer (CC) was investigated. mRNA [...] Read more.
G protein-coupled receptor 55 (GPR55) probably plays a role in innate immunity and tumor immunosurveillance through its effect on immune cells, such as T cells and NK cells. In this study, the prognostic value of GPR55 in colon cancer (CC) was investigated. mRNA expression levels of GPR55 were determined in 382 regional lymph nodes of 121 CC patients with 12 years observation time after curative surgery. The same clinical material had previously been analyzed for expression levels of CEA, CXCL16, CXCL17, GPR35 V2/3 and LGR5 mRNAs. Clinical cutoffs of 0.1365 copies/18S rRNA unit for GPR55 and 0.1481 for the GPR55/CEA ratio were applied to differentiate between the high- and low-GPR55 expression groups. Kaplan–Meier survival analysis and Cox regression risk analysis were used to determine prognostic value. Improved discrimination between the two groups was achieved by combining GPR55 with CEA, CXCL16 or CXCL17 compared with GPR55 alone. The best result was obtained using the GPR55/CEA ratio, with an increased mean survival time of 14 and 33 months at 5 and 12 years observation time, respectively (p = 0.0003 and p = 0.003) for the high-GPR55/CEA group. The explanation for the observed improvement is most likely that GPR55 is a marker for T cells and B cells in lymph nodes, whereas CEA, CXCL16 and CXCL17, are markers for tumor cells of epithelial origin. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
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17 pages, 2782 KiB  
Article
Clinical Significance of Stem Cell Biomarkers EpCAM, LGR5 and LGR4 mRNA Levels in Lymph Nodes of Colon Cancer Patients
by Manar AbdelMageed, Hager Tarek H. Ismail, Lina Olsson, Gudrun Lindmark, Marie-Louise Hammarström, Sten Hammarström and Basel Sitohy
Int. J. Mol. Sci. 2022, 23(1), 403; https://doi.org/10.3390/ijms23010403 - 30 Dec 2021
Cited by 16 | Viewed by 2353
Abstract
The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically [...] Read more.
The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan-Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA copies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12-year follow-up (p = 0.022, p = 0.005 and p = 0.011, respectively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
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Review

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23 pages, 439 KiB  
Review
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
by Francesca Rebuzzi, Paola Ulivi and Gianluca Tedaldi
Int. J. Mol. Sci. 2023, 24(3), 2137; https://doi.org/10.3390/ijms24032137 - 21 Jan 2023
Cited by 21 | Viewed by 6530
Abstract
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some [...] Read more.
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li–Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz–Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
20 pages, 1251 KiB  
Review
Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers
by Andrei Havasi, Daniel Sur, Simona Sorana Cainap, Cristian-Virgil Lungulescu, Laura-Ioana Gavrilas, Calin Cainap, Catalin Vlad and Ovidiu Balacescu
Int. J. Mol. Sci. 2022, 23(3), 1109; https://doi.org/10.3390/ijms23031109 - 20 Jan 2022
Cited by 11 | Viewed by 2866
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend [...] Read more.
Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
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Other

13 pages, 8120 KiB  
Case Report
ETV6::NTRK3 Fusion-Positive Wild-Type Gastrointestinal Stromal Tumor (GIST) with Abundant Lymphoid Infiltration (TILs and Tertiary Lymphoid Structures): A Report on a New Case with Therapeutic Implications and a Literature Review
by Isidro Machado, Reyes Claramunt-Alonso, Javier Lavernia, Ignacio Romero, María Barrios, María José Safont, Nuria Santonja, Lara Navarro, José Antonio López-Guerrero and Antonio Llombart-Bosch
Int. J. Mol. Sci. 2024, 25(7), 3707; https://doi.org/10.3390/ijms25073707 - 26 Mar 2024
Cited by 3 | Viewed by 1418
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) [...] Read more.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Gastrointestinal Tumors)
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