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Molecular Alterations in GastroIntestinal Pre-invasive Lesions

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 25542

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Special Issue Editors

Prof. Dr. Luca Saragoni

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Guest Editor

Department of Pathology, G.B.Morgagni–L.Pierantoni Hospital, Forlì, Italy
Interests: gastrointestinal pathology; gastric cancer
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Matteo Fassan

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Guest Editor

Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Giustiniani, 35128 Padua, Italy
Interests: colorectal cancer; gastric cancer; dysplasia; molecular carcinogenesis; predictive biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleguaes,

The relatively recent comprehensive molecular characterization of gastrointestinal tumors has demonstrated that similar oncogenetic pathways are shared among different types of cancers. This represents the biological rationale for the development and introduction into clinical practice of targeted therapies and for the optimization of the already available chemotherapeutic drugs. Moreover, significant intra-tumor genomic and epigenomic heterogeneity has been observed, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Despite these important information, complete molecular data on pre-invasive lesions of the gastrointestinal tract are still limited, significantly affecting the diagnostic process and treatment of gastrointestinal “early” lesions. The research topic aims to study: (i) the clinico-pathological features and their matched molecular characteristics distinguishing pre-invasive (early) gastrointestinal lesions; (ii) the identification of novel molecular markers, which can be useful in the identification of the neoplastic precursors/preinvasive lesions; (iii) the identification of novel molecular biomarkers to be implemented in the secondary prevention strategies of invasive gastrointestinal tumors.

Prof. Dr. Luca Saragoni
Prof. Dr. Matteo Fassan
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 cancer
early diagnosis
molecular markers
non-invasive treatments.

Published Papers (7 papers)

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Research

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27 pages, 9926 KiB

Open AccessArticle

Macrophage Inflammatory Proteins (MIPs) Contribute to Malignant Potential of Colorectal Polyps and Modulate Likelihood of Cancerization Associated with Standard Risk Factors

by Jarosław Wierzbicki, Iwona Bednarz-Misa, Łukasz Lewandowski, Artur Lipiński, Anna Kłopot, Katarzyna Neubauer and Małgorzata Krzystek-Korpacka

Int. J. Mol. Sci. 2024, 25(3), 1383; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031383 - 23 Jan 2024

Viewed by 614

Abstract

Better understanding of molecular changes leading to neoplastic transformation is prerequisite to optimize risk assessment and chemopreventive and surveillance strategies. Data on macrophage inflammatory proteins (MIPs) in colorectal carcinogenesis are scanty and their clinical relevance remains unknown. Therefore, transcript and protein expression of CCL3, CCL4, CXCL2, and CCL19 were determined in 173 and 62 patients, respectively, using RT-qPCR and immunohistochemistry with reference to polyps’ characteristics. The likelihood of malignancy was modeled using probit regression. With the increasing malignancy potential of hyperplastic–tubular–tubulo-villous–villous polyps, the expression of CCL3, CCL4, and CCL19 in lesions decreased. CCL19 expression decreased also in normal mucosa while that of CXCL2 increased. Likewise, lesion CCL3 and lesion and normal mucosa CCL19 decreased and normal CXCL2 increased along the hyperplasia–low–high dysplasia grade. The bigger the lesion, the lower CCL3 and higher CXCL2 in normal mucosa. Singular polyps had higher CCL3, CCL4, and CCL19 levels in normal mucosa. CCL3, CCL4 and CXCL2 modulated the likelihood of malignancy associated with traditional risk factors. There was no correlation between the protein and mRNA expression of CCL3 and CCL19. In summary, the polyp-adjacent mucosa contributes to gaining potential for malignancy by polyps. MIPs may help in specifying cancerization probability estimated based on standard risk factors. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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13 pages, 6151 KiB

Open AccessArticle

The Adaptive Immune Landscape of the Colorectal Adenoma–Carcinoma Sequence

by João Augusto Freitas, Irene Gullo, Diogo Garcia, Sara Miranda, Louisa Spaans, Lídia Pinho, Joana Reis, Fabiana Sousa, Manuela Baptista, Carlos Resende, Dina Leitão, Cecília Durães, José Luis Costa, Fátima Carneiro and José Carlos Machado

Int. J. Mol. Sci. 2021, 22(18), 9791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189791 - 10 Sep 2021

Cited by 4 | Viewed by 2796

Abstract

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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Review

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17 pages, 1670 KiB

Open AccessReview

Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions

by Gianluca Businello, Valentina Angerilli, Paola Parente, Stefano Realdon, Edoardo Savarino, Fabio Farinati, Federica Grillo, Alessandro Vanoli, Francesca Galuppini, Silvia Paccagnella, Gianmaria Pennelli, Luca Mastracci, Luca Saragoni and Matteo Fassan

Int. J. Mol. Sci. 2021, 22(18), 9950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189950 - 14 Sep 2021

Cited by 11 | Viewed by 4604

Abstract

Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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15 pages, 1362 KiB

Open AccessReview

From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

by Martina Lepore Signorile, Vittoria Disciglio, Gabriella Di Carlo, Antonio Pisani, Cristiano Simone and Giuseppe Ingravallo

Int. J. Mol. Sci. 2021, 22(13), 6767; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136767 - 23 Jun 2021

Cited by 9 | Viewed by 3159

Abstract

Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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10 pages, 1449 KiB

Open AccessReview

Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer

by Serena Battista, Maria Raffaella Ambrosio, Francesco Limarzi, Graziana Gallo and Luca Saragoni

Int. J. Mol. Sci. 2021, 22(13), 6652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136652 - 22 Jun 2021

Cited by 21 | Viewed by 3897

Abstract

Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa’s cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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12 pages, 1022 KiB

Open AccessReview

Molecular Alterations in Gastric Intestinal Metaplasia

by Paulius Jonaitis, Limas Kupcinskas and Juozas Kupcinskas

Int. J. Mol. Sci. 2021, 22(11), 5758; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115758 - 28 May 2021

Cited by 11 | Viewed by 5755

Abstract

Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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25 pages, 3382 KiB

Open AccessReview

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

by Alessandro Vanoli, Federica Grillo, Daniela Furlan, Giovanni Arpa, Oneda Grami, Camilla Guerini, Roberta Riboni, Luca Mastracci and Antonio Di Sabatino

Int. J. Mol. Sci. 2021, 22(9), 4388; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094388 - 22 Apr 2021

Cited by 5 | Viewed by 3608

Abstract

The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, MUTYH-associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn’s disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn’s disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions. Full article

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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