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Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment
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Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 January 2023) | Viewed by 16777

Special Issue Editors

Dr. Lucio Bertario

E-Mail Website
Guest Editor
Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, 20141 Milan, Italy
Interests: colorectal cancer; colon cancer; familial adenomatous polyposis; Lynch syndrome
Dr. Bernardo Bonanni

E-Mail Website
Guest Editor
Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, 20141 Milan, Italy
Interests: cancer genetics and prevention; E-cadherin; CDH1 mutations; hereditary cancers
Special Issues, Collections and Topics in MDPI journals
Dr. Davide Serrano

E-Mail Website
Guest Editor
Department of Experimental Oncology, European Institute of Oncology, Milano, Italy
Interests: cancer preventive medicine; hereditary syndromes, particularly of breast and gastrointestinal tract; cascade screening and surveillance programs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The vast majority of human cancers begin with an accumulation of genetic abnormalities leading to cancer stem cells, and the development to cancer clinical manifestation. A clear example of this progressive accumulation of DNA damage was made clear with the adeno-carcinoma progression for colorectal cancer. The most common oncogenes, that is, tumor suppressor genes, include those related to cell-cycle checkpoint, DNA repair, DNA damage repair recognition, apoptosis, and cell differentiation. Cancer cells may further accumulate more abnormalities, developing tumors with heterogeneity. All these mutations are commonly acquired at the somatic level.

Even though they are relatively rare overall, there are a substantial number of hereditary syndromes affecting the gastrointestinal tract. Hence the need to promote molecular and genetic studies to find possible actionable application in the diagnosis and clinical management of gastrointestinal cancers, which still represent a real social problem.

This background led us to propose a dedicated Special Issue with the title “Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment”. The creation of a focused Special Issue will facilitate data sharing that may improve the personalization of prevention programs and precision therapeutic protocols for individuals at higher cancer risk.

Dr. Lucio Bertario
Dr. Bernardo Bonanni
Dr. Davide Serrano
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. Genes is an international peer-reviewed open access monthly 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 2600 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

  • cancer susceptibility gene
  • gastrointestinal cancer
  • hereditary syndromes
  • prognostic genes
  • predictive genes
  • genetic carrier screening
  • preventive medicine
  • precision medicine

Published Papers (10 papers)

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Editorial

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4 pages, 194 KiB  
Editorial
Editorial for the Special Issue “Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment”
by Monica Marabelli, Lucio Bertario and Davide Serrano
Genes 2023, 14(9), 1821; https://doi.org/10.3390/genes14091821 - 20 Sep 2023
Viewed by 725
Abstract
According to the latest estimate from GLOBOCAN 2020, approximately 18 [...] Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)

Research

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16 pages, 2820 KiB  
Article
Tribbles Genes in Gastric Cancer: A Tumor-Suppressive Role for TRIB2
by Alessia Foscarini, Rossella Tricarico, Federica Gentile, Swapna Satam, Hermine Mohr, Endre Kiss-Toth, Guglielmina Nadia Ranzani and Natalia Simona Pellegata
Genes 2024, 15(1), 26; https://doi.org/10.3390/genes15010026 - 23 Dec 2023
Viewed by 984
Abstract
Tribbles pseudokinases (TRIB1-3) are important signaling modulators involved in several cancers. However, their function in gastric cancer (GC) remains undefined. GC is still a deadly disease since the lack of sensitive and specific biomarkers for early diagnosis and therapy response prediction negatively affects [...] Read more.
Tribbles pseudokinases (TRIB1-3) are important signaling modulators involved in several cancers. However, their function in gastric cancer (GC) remains undefined. GC is still a deadly disease since the lack of sensitive and specific biomarkers for early diagnosis and therapy response prediction negatively affects patients’ outcome. The identification of novel molecular players may lead to more effective diagnostic and therapeutic avenues. Therefore, we investigated the role of TRIB genes in gastric tumorigenesis. Data mining of the TCGA dataset revealed that chromosomal instability (CIN) tumors have lower TRIB2 and higher TRIB3 expression versus microsatellite instability (MSI)-high tumors, while TRIB1 levels are similar in both tumor types. Moreover, in CIN tumors, low TRIB2 expression is significantly associated with aggressive stage IV disease. As no studies on TRIB2 in GC are available, we focused on this gene for further in vitro analyses. We checked the effect of TRIB2 overexpression (OE) on MKN45 and NCI-N87 CIN GC cell lines. In MKN45 cells, TRIB2 OE reduced proliferation and colony formation ability and induced G2/M arrest, while it decreased the proliferation and cell motility of NCI-N87 cells. These effects were not mediated by the MAPK pathway. Our results suggest a tumor-suppressive function of TRIB2 in GC with a CIN phenotype. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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12 pages, 1578 KiB  
Article
MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis
by Ileana Wanda Carnevali, Giulia Cini, Laura Libera, Nora Sahnane, Sofia Facchi, Alessandra Viel, Fausto Sessa and Maria Grazia Tibiletti
Genes 2023, 14(11), 2060; https://doi.org/10.3390/genes14112060 - 09 Nov 2023
Cited by 3 | Viewed by 1562
Abstract
(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection [...] Read more.
(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However, MLH1 hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of MLH1 protein expression and microsatellite instability. All cases were investigated for MLH1 promoter methylation and MLH1/PMS2 germline variants. (3) Results: Somatic MLH1 promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of MLH1 germline pathogenic variants. In two families, primary and secondary MLH1 epimutations were demonstrated. (4) Conclusions: MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient’s family and personal history. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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13 pages, 642 KiB  
Article
Hereditary Gastric Cancer: Single-Gene or Multigene Panel Testing? A Mono-Institutional Experience
by Mariarosaria Calvello, Monica Marabelli, Sara Gandini, Elena Marino, Loris Bernard, Matteo Dal Molin, Giulia Di Cola, Cristina Zanzottera, Giovanni Corso, Nicola Fazio, Lorenzo Gervaso, Uberto Fumagalli Romario, Massimo Barberis, Aliana Guerrieri-Gonzaga, Lucio Bertario, Davide Serrano and Bernardo Bonanni
Genes 2023, 14(5), 1077; https://doi.org/10.3390/genes14051077 - 13 May 2023
Cited by 3 | Viewed by 1569
Abstract
Gastric cancer (GC) has long been a ‘Cinderella’ among hereditary cancers. Until recently, single-gene testing (SGT) was the only approach to identify high-risk individuals. With the spread of multigene panel testing (MGPT), a debate arose on the involvement of other genes, particularly those [...] Read more.
Gastric cancer (GC) has long been a ‘Cinderella’ among hereditary cancers. Until recently, single-gene testing (SGT) was the only approach to identify high-risk individuals. With the spread of multigene panel testing (MGPT), a debate arose on the involvement of other genes, particularly those pertaining to homologous recombination (HR) repair. We report our mono-institutional experience in genetic counseling and SGT for 54 GC patients, with the detection of nine pathogenic variants (PVs) (9/54:16.7%). Seven out of fifty (14%) patients who underwent SGT for unknown mutations were carriers of a PV in CDH1 (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), and MSH2 (n = 1), while one patient (2%) carried two variants of unknown significance (VUSs). CDH1 and MSH2 emerged as genes involved in early-onset diffuse and later-onset intestinal GCs, respectively. We additionally conducted MGPT on 37 patients, identifying five PVs (13.5%), including three (3/5:60%) in an HR gene (BRCA2, ATM, RAD51D) and at least one VUS in 13 patients (35.1%). Comparing PV carriers and non-carriers, we observed a statistically significant difference in PVs between patients with and without family history of GC (p-value: 0.045) or Lynch-related tumors (p-value: 0.036). Genetic counseling remains central to GC risk assessment. MGPT appeared advantageous in patients with unspecific phenotypes, although it led to challenging results. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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11 pages, 20528 KiB  
Article
Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations
by Andrea Remo, Federica Grillo, Luca Mastracci, Michele Simbolo, Matteo Fassan, Maria Paola Cecchini, Giuseppe Miscio, Antonio Sassano, Paola Parente, Alessandro Vanoli, Giovanna Sabella, Guido Giordano, Emanuele Damiano Urso, Luigi Cerulo, Aldo Scarpa, Francesco Fiorica and Massimo Pancione
Genes 2023, 14(5), 984; https://doi.org/10.3390/genes14050984 - 27 Apr 2023
Cited by 3 | Viewed by 1409
Abstract
A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and [...] Read more.
A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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15 pages, 69749 KiB  
Article
Whole Exome Sequencing Study Suggests an Impact of FANCA, CDH1 and VEGFA Genes on Diffuse Gastric Cancer Development
by Alfiia Nurgalieva, Lilia Galliamova, Natalia Ekomasova, Maria Yankina, Dina Sakaeva, Ruslan Valiev, Darya Prokofyeva, Murat Dzhaubermezov, Yuliya Fedorova, Shamil Khusnutdinov and Elza Khusnutdinova
Genes 2023, 14(2), 280; https://doi.org/10.3390/genes14020280 - 21 Jan 2023
Cited by 2 | Viewed by 1620
Abstract
Gastric cancer (GC) is one of the most common cancer types in the world with a high mortality rate. Hereditary predisposition for GC is not fully elucidated so far. The aim of this study was identification of possible new candidate genes, associated with [...] Read more.
Gastric cancer (GC) is one of the most common cancer types in the world with a high mortality rate. Hereditary predisposition for GC is not fully elucidated so far. The aim of this study was identification of possible new candidate genes, associated with the increased risk of gastric cancer development. Whole exome sequencing (WES) was performed on 18 DNA samples from adenocarcinoma specimens and non-tumor-bearing healthy stomach tissue from the same patient. Three pathogenic variants were identified: c.1320+1G>A in the CDH1 gene and c.27_28insCCCAGCCCCAGCTACCA (p.Ala9fs) of the VEGFA gene were found only in the tumor tissue, whereas c.G1874C (p.Cys625Ser) in the FANCA gene was found in both the tumor and normal tissue. These changes were found only in patients with diffuse gastric cancer and were absent in the DNA of healthy donors. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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10 pages, 276 KiB  
Article
Association between INDELs in MicroRNAs and Susceptibility to Gastric Cancer in Amazonian Population
by Antonio A. C. Modesto, Milene R. de Moraes, Cristina M. D. Valente, Marta S. C. R. Costa, Diana F. da V. B. Leal, Esdras E. B. Pereira, Marianne R. Fernandes, Jhully A. dos S. Pinheiro, Karla B. C. C. Pantoja, Fabiano C. Moreira, Rommel M. R. Burbano, Paulo P. de Assumpção, Ney P. C. dos Santos and Sidney E. B. dos Santos
Genes 2023, 14(1), 60; https://doi.org/10.3390/genes14010060 - 24 Dec 2022
Cited by 1 | Viewed by 1914
Abstract
Gastric cancer (GC) is a multifactorial, complex, and aggressive disease with a prevalence of one million new cases and high global mortality. Factors such as genetic, epigenetic, and environmental changes contribute to the onset and progression of the disease. Identification of INDELs in [...] Read more.
Gastric cancer (GC) is a multifactorial, complex, and aggressive disease with a prevalence of one million new cases and high global mortality. Factors such as genetic, epigenetic, and environmental changes contribute to the onset and progression of the disease. Identification of INDELs in miRNA and its target sites in current studies showed an important role in the development of cancer. In GC, miRNAs act as oncogenes or tumor suppressors, favoring important cancer pathways, such as cell proliferation and migration. This work aims to investigate INDELs in the coding region of miRNAs (hsa-miR-302c, hsa-miR-548AJ-2, hsa-miR-4274, hsa-miR-630, hsa-miR-516B-2, hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920, has-mir-3171, and hsa-miR-3652) that may be associated with susceptibility and clinical variants of gastric cancer. For this study, 301 patients with GC and 145 individuals from the control group were selected from an admixed population in the Brazilian Amazon. The results showed the hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920 and hsa-miR-3652 variants were associated with gastric cancer susceptibility. The hsa-miR-4463 was significantly associated with clinical features of GC such as diffuse gastric tumor histological type, “non-cardia” localization region, and early onset. Our findings indicated that INDELs could be potentially functional genetic variants for gastric cancer risk. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
17 pages, 6857 KiB  
Article
Comprehensive Analysis of Potential Prognostic Values of ANGPTLs in Colorectal Cancer
by Yang Zhang, Xuyang Yang, Sicheng Liu, Zixuan Zhuang, Mingtian Wei, Xiangbing Deng and Ziqiang Wang
Genes 2022, 13(12), 2215; https://doi.org/10.3390/genes13122215 - 25 Nov 2022
Cited by 4 | Viewed by 1516
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. CRC recurrence and metastasis cause poor prognosis. ANGPTLs (angiopoietin-like proteins) are a family of proteins that are widely involved in metabolic disease and tumorigenesis. The roles of ANGPTLs in [...] Read more.
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. CRC recurrence and metastasis cause poor prognosis. ANGPTLs (angiopoietin-like proteins) are a family of proteins that are widely involved in metabolic disease and tumorigenesis. The roles of ANGPTLs in CRC are still controversial and deserve further research. In this study, several databases were employed to explore the expression profiles, prognostic values, genetic alterations, potential biological function, and immune infiltration correlation of ANGPTLs in CRC. The expression of ANGPTL4 was significantly positively correlated with the stage of CRC. Therefore, cell and molecular experiments were further performed to explore the roles of ANGPTL4. Our results showed that the transcriptions of ANGPTLs in colon cancer and rectal cancer tissues were lower than those in normal tissues, but the protein expression varied among different ANGPTLs. In addition, the high expression of ANGPTLs led to a relatively poor oncological outcome. Specifically, the expression of ANGPTL4 is significantly positively correlated with the stage of CRC. Further investigation revealed that ANGPTLs are mainly involved in signal transduction and the regulation of transcription, while KEGG pathway analyses demonstrated pathways in cancer. Additionally, we also observed that ANGPTL4 could promote the proliferation and migration of CRC cells, and four specific small molecule compounds had potential ANGPTL4-binding capabilities, suggesting the clinical application of these small molecule compounds on CRC treatment. Our findings imply the prognostic values and potential therapeutic targets of ANGPTLs in CRC. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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Review

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20 pages, 2122 KiB  
Review
Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability—Lessons from Colorectal Cancer
by Luana Greco, Federica Rubbino, Arianna Dal Buono and Luigi Laghi
Genes 2023, 14(6), 1169; https://doi.org/10.3390/genes14061169 - 27 May 2023
Cited by 4 | Viewed by 2439
Abstract
Microsatellite instability (MSI) can be found in 15–20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment [...] Read more.
Microsatellite instability (MSI) can be found in 15–20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment of CRC. MSI tumors display a strong lymphocytic activation and a shift toward a tumoral microenvironment restraining metastatic potential and ensuing in a high responsiveness to immunotherapy of MSI CRC. Indeed, neoplastic cells with an MMR defect overexpress several immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1(PD-L1), that can be pharmacologically targeted, allowing for the revival the cytotoxic immune response toward the tumor. This review aims to illustrate the role of MSI in the tumor biology of colorectal cancer, focusing on the immune interactions with the microenvironment and their therapeutic implications. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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21 pages, 1707 KiB  
Review
Malignancies in Patients with Celiac Disease: Diagnostic Challenges and Molecular Advances
by Mariia Ivanova, Luca Bottiglieri, Elham Sajjadi, Konstantinos Venetis and Nicola Fusco
Genes 2023, 14(2), 376; https://doi.org/10.3390/genes14020376 - 31 Jan 2023
Cited by 5 | Viewed by 2269
Abstract
Celiac disease (CD) is a multiorgan autoimmune disorder of the chronic intestinal disease group characterized by duodenal inflammation in genetically predisposed individuals, precipitated by gluten ingestion. The pathogenesis of celiac disease is now widely studied, overcoming the limits of the purely autoimmune concept [...] Read more.
Celiac disease (CD) is a multiorgan autoimmune disorder of the chronic intestinal disease group characterized by duodenal inflammation in genetically predisposed individuals, precipitated by gluten ingestion. The pathogenesis of celiac disease is now widely studied, overcoming the limits of the purely autoimmune concept and explaining its hereditability. The genomic profiling of this condition has led to the discovery of numerous genes involved in interleukin signaling and immune-related pathways. The spectrum of disease manifestations is not limited to the gastrointestinal tract, and a significant number of studies have considered the possible association between CD and neoplasms. Patients with CD are found to be at increased risk of developing malignancies, with a particular predisposition of certain types of intestinal cancer, lymphomas, and oropharyngeal cancers. This can be partially explained by common cancer hallmarks present in these patients. The study of gut microbiota, microRNAs, and DNA methylation is evolving to find the any possible missing links between CD and cancer incidence in these patients. However, the literature is extremely mixed and, therefore, our understanding of the biological interplay between CD and cancer remains limited, with significant implications in terms of clinical management and screening protocols. In this review article, we seek to provide a comprehensive overview of the genomics, epigenomics, and transcriptomics data on CD and its relation to the most frequent types of neoplasms that may occur in these patients. Full article
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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