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Colorectal Cancer: A Molecular Genetics Perspective

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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: 10 June 2024 | Viewed by 13567

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Special Issue Editor

Dr. Ehsan Gharib

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Guest Editor

1. Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
2. Atlantic Cancer Research Institute, Université de Moncton, Moncton, NB E1C 8X3, Canada
Interests: cancer genetics; cancer biology; cancer biomarkers; non-coding RNAs

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is a heterogeneous disease caused by an accumulation of genetic mutations. Recent advances in genomic investigations have resulted in a rapid increase in our understanding of CRC’s molecular basis, and a new era of targeted therapies has emerged that tailored treatment regimens to the mutation profiles of individual tumors. This horizon would be achievable through gaining a working knowledge of the pathological mechanisms that drive the malignancy. To this goal, we encourage scientists to publish their experimental, theoretical, and computational results in as much detail as possible in the “Colorectal Cancer: A Molecular Genetics Perspective” Special Issue provided by the International Journal of Molecular Sciences (IJMS).

Dr. Ehsan Gharib
Guest Editor

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Keywords

colorectal cancer
chromosomal and Microsatellite instability
CpG island methylator phenotype
molecular characteristics
early diagnosis
targeted therapy

Published Papers (10 papers)

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Research

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23 pages, 19818 KiB

Open AccessArticle

The Construction of a Multi-Gene Risk Model for Colon Cancer Prognosis and Drug Treatments Prediction

by Liyang Gao, Ye Tian and Erfei Chen

Int. J. Mol. Sci. 2024, 25(7), 3954; https://doi.org/10.3390/ijms25073954 - 2 Apr 2024

Viewed by 678

Abstract

In clinical practice, colon cancer is a prevalent malignant tumor of the digestive system, characterized by a complex and progressive process involving multiple genes and molecular pathways. Historically, research efforts have primarily focused on investigating individual genes; however, our current study aims to explore the collective impact of multiple genes on colon cancer and to identify potential therapeutic targets associated with these genes. For this research, we acquired the gene expression profiles and RNA sequencing data of colon cancer from TCGA. Subsequently, we conducted differential gene expression analysis using R, followed by GO and KEGG pathway enrichment analyses. To construct a protein–protein interaction (PPI) network, we selected survival-related genes using the log-rank test and single-factor Cox regression analysis. Additionally, we performed LASSO regression analysis, immune infiltration analysis, mutation analysis, and cMAP analysis, as well as an investigation into ferroptosis. Our differential expression and survival analyses identified 47 hub genes, and subsequent LASSO regression analysis refined the focus to 23 key genes. These genes are closely linked to cancer metastasis, proliferation, apoptosis, cell cycle regulation, signal transduction, cancer microenvironment, immunotherapy, and neurodevelopment. Overall, the hub genes discovered in our study are pivotal in colon cancer and are anticipated to serve as important biological markers for the diagnosis and treatment of the disease. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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12 pages, 1140 KiB

Open AccessCommunication

Plasma Circulating mRNA Profile for the Non-Invasive Diagnosis of Colorectal Cancer Using NanoString Technologies

by Hin Fung Tsang, Xiao Meng Pei, Yin Kwan Evelyn Wong and Sze Chuen Cesar Wong

Int. J. Mol. Sci. 2024, 25(5), 3012; https://doi.org/10.3390/ijms25053012 - 5 Mar 2024

Viewed by 713

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer deaths in developed countries. Early CRC may have no symptoms and symptoms usually appear with more advanced diseases. Regular screening can identify people who are at increased risk of CRC in order to offer earlier treatment. A cost-effective non-invasive platform for the screening and monitoring of CRC patients allows early detection and appropriate treatment of the disease, and the timely application of adjuvant therapy after surgical operation is needed. In this study, a cohort of 71 plasma samples that include 48 colonoscopy- and histopathology-confirmed CRC patients with TNM stages I to IV were recruited between 2017 and 2019. Plasma mRNA profiling was performed in CRC patients using NanoString nCounter. Normalized data were analyzed using a Mann–Whitney U test to determine statistically significant differences between samples from CRC patients and healthy subjects. A multiple-group comparison of clinical phenotypes was performed using the Kruskal–Wallis H test for statistically significant differences between multiple groups. Among the 27 selected circulating mRNA markers, all of them were found to be overexpressed (gene expression fold change > 2) in the plasma of patients from two or more CRC stages. In conclusion, NanoString-based targeted plasma CRC-associated mRNAs circulating the marker panel that can significantly distinguish CRC patients from a healthy population were developed for the non-invasive diagnosis of CRC using peripheral blood samples. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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13 pages, 1226 KiB

Open AccessArticle

The Role of KRAS Mutation in Colorectal Cancer-Associated Thrombosis

by Radu Andrei Emilescu, Mariana Jinga, Horia Teodor Cotan, Ana Maria Popa, Cristina Maria Orlov-Slavu, Mihaela Cristina Olaru, Cristian Ion Iaciu, Andreea Ioana Parosanu, Mihaela Moscalu and Cornelia Nitipir

Int. J. Mol. Sci. 2023, 24(23), 16930; https://doi.org/10.3390/ijms242316930 - 29 Nov 2023

Viewed by 844

Abstract

Venous thromboembolic events (VTE) are common in patients with colorectal cancer (CRC) and represent a significant contributor to morbidity and mortality. Risk stratification is paramount in deciding the initiation of thromboprophylaxis and is calculated using scores that include tumor location, laboratory values, patient clinical characteristics, and tumor burden. Commonly used risk scores do not include the presence of molecular aberrations as a variable. This retrospective study aims to confirm the link between KRAS-activating mutations and the development of VTE in CRC. A total of 166 patients were included in this study. They were split into two cohorts based on KRAS mutational status. We evaluated the frequency and mean time to VTE development stratified by the presence of KRAS mutations. Patients with mutant KRAS had an odds ratio (OR) of 2.758 for VTE compared to KRAS wild-type patients, with an increased risk of thrombosis being maintained in KRAS mutant patients even after adjusting for other known VTE risk factors. Taking into account the results of this study, KRAS mutation represents an independent risk factor for VTE. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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11 pages, 495 KiB

Open AccessArticle

KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer

by Maria Radanova, Galya Mihaylova, George St. Stoyanov, Vyara Draganova, Aleksandar Zlatarov, Nikola Kolev, Eleonora Dimitrova, Nikolay Conev and Diana Ivanova

Int. J. Mol. Sci. 2023, 24(16), 12753; https://doi.org/10.3390/ijms241612753 - 13 Aug 2023

Viewed by 1191

Abstract

RAS somatic variants are predictors of resistance to anti-EGFR therapy for colorectal cancer (CRC) and affect the outcome of the disease. Our study aimed to evaluate the frequency of RAS, with a focus on KRAS variants, and their association with tumor location and some clinicopathological characteristics in Bulgarian CRC patients. We prospectively investigated 236 patients with advanced and metastatic CRC. Genomic DNA was extracted from FFPE tumor tissue samples, and commercially available kits were used to detect RAS gene somatic mutations via real-time PCR. A total of 115 (48.73%) patients tested positive for RAS mutations, with 106 (44.92%) testing positive for KRAS mutations. The most common mutation in exon 2 was c.35G>T p.Gly12Val (32.56%). We did not find a significant difference in KRAS mutation frequency according to tumor location. However, patients with a mutation in exon 4 of KRAS were 3.23 times more likely to have a tumor in the rectum than in other locations (95% CI: 1.19–8.72, p = 0.021). Studying the link between tumor location and KRAS mutations in exon 4 is crucial for better characterizing CRC patients. Further research with larger cohorts, especially in rectal cancer patients, could provide valuable insights for patient follow-up and treatment selection. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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13 pages, 1441 KiB

Open AccessArticle

PINK1 Immunoexpression Predicts Survival in Patients Undergoing Hepatic Resection for Colorectal Liver Metastases

by Juan Carlos Celis-Pinto, Adela Alonso Fernández-Velasco, María Daniela Corte-Torres, Jorge Santos-Juanes, Noelia Blanco-Agudín, Kelvin Manuel Piña Batista, Jesús Merayo-Lloves, Luis M. Quirós and Iván Fernández-Vega

Int. J. Mol. Sci. 2023, 24(7), 6506; https://doi.org/10.3390/ijms24076506 - 30 Mar 2023

Viewed by 1471

Abstract

PTEN-induced kinase-1 (PINK1) is the initiator of the canonical mitophagy pathway. Our aim was to study the immunoexpression of PINK1 in surgical specimens from ninety patients with metastatic colorectal adenocarcinoma (CRC) to the liver (CRLM). Tissue arrays were produced, and immunohistochemical studies were analyzed by the H-Score method. The mean immunoexpression of PINK1 in normal tissues was between 40 to 100 points. In tumoral tissues, positive PINK1 immunoexpression was observed in all samples, and no differences were noted between CRCs. In CRLMs, a significant under-expression was noted for PINK1 from the rectum (71.3 ± 30.8; p < 0.042) compared to other sites. Altered PINK1 immunoexpression in CRCs, either higher than 100 points or lower than 40 points, was associated with worse overall survival (OS) (p < 0.012) due to a shorter post-metastatic survival (PMS) (p < 0.023), and it was found to be a significant independent predictor of prognosis in a multivariate model for OS and PMS (HR = 1.972, 95% CI 0.971–4.005; p = 0.022. HR = 2.023, 95% CI 1.003–4.091; p = 0.037, respectively). In conclusion, altered PINK1 immunoexpression determined in CRCs with resected CRLM predicts a worse prognosis, possibly due to the abnormal function of mitophagy. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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Review

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26 pages, 942 KiB

Open AccessReview

Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications

by Qing Cao, Ye Tian, Zhiyi Deng, Fangfang Yang and Erfei Chen

Int. J. Mol. Sci. 2024, 25(6), 3358; https://doi.org/10.3390/ijms25063358 - 15 Mar 2024

Viewed by 975

Abstract

Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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20 pages, 2141 KiB

Open AccessReview

Genetic Alterations of NF-κB and Its Regulators: A Rich Platform to Advance Colorectal Cancer Diagnosis and Treatment

by Faranak Alipourgivi, Aishat Motolani, Alice Y. Qiu, Wenan Qiang, Guang-Yu Yang, Shuibing Chen and Tao Lu

Int. J. Mol. Sci. 2024, 25(1), 154; https://doi.org/10.3390/ijms25010154 - 21 Dec 2023

Cited by 2 | Viewed by 1173

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States, with an estimated 52,000 deaths in 2023. Though significant progress has been made in both diagnosis and treatment of CRC in recent years, genetic heterogeneity of CRC—the culprit for possible CRC relapse and drug resistance, is still an insurmountable challenge. Thus, developing more effective therapeutics to overcome this challenge in new CRC treatment strategies is imperative. Genetic and epigenetic changes are well recognized to be responsible for the stepwise development of CRC malignancy. In this review, we focus on detailed genetic alteration information about the nuclear factor (NF)-κB signaling, including both NF-κB family members, and their regulators, such as protein arginine methyltransferase 5 (PRMT5), and outer dynein arm docking complex subunit 2 (ODAD2, also named armadillo repeat-containing 4, ARMC4), etc., in CRC patients. Moreover, we provide deep insight into different CRC research models, with a particular focus on patient-derived xenografts (PDX) and organoid models, and their potential applications in CRC research. Genetic alterations on NF-κB signaling components are estimated to be more than 50% of the overall genetic changes identified in CRC patients collected by cBioportal for Cancer Genomics; thus, emphasizing its paramount importance in CRC progression. Consequently, various genetic alterations on NF-κB signaling may hold great promise for novel therapeutic development in CRC. Future endeavors may focus on utilizing CRC models (e.g., PDX or organoids, or isogenic human embryonic stem cell (hESC)-derived colonic cells, or human pluripotent stem cells (hPSC)-derived colonic organoids, etc.) to further uncover the underpinning mechanism of these genetic alterations in NF-κB signaling in CRC progression. Moreover, establishing platforms for drug discovery in dishes, and developing Biobanks, etc., may further pave the way for the development of innovative personalized medicine to treat CRC in the future. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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17 pages, 1498 KiB

Open AccessReview

Clusterin Expression in Colorectal Carcinomas

by Teresa Téllez, Desirée Martin-García, Maximino Redondo and Marilina García-Aranda

Int. J. Mol. Sci. 2023, 24(19), 14641; https://doi.org/10.3390/ijms241914641 - 27 Sep 2023

Cited by 2 | Viewed by 1141

Abstract

Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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24 pages, 1529 KiB

Open AccessReview

Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review

by Fernand Bteich, Mahshid Mohammadi, Terence Li, Muzaffer Ahmed Bhat, Amalia Sofianidi, Ning Wei and Chaoyuan Kuang

Int. J. Mol. Sci. 2023, 24(15), 12030; https://doi.org/10.3390/ijms241512030 - 27 Jul 2023

Cited by 4 | Viewed by 3333

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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Other

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12 pages, 1407 KiB

Open AccessCase Report

A Novel DNA Variant in SMARCA4 Gene Found in a Patient Affected by Early Onset Colon Cancer

by Federica Di Maggio, Giuseppe Boccia, Marcella Nunziato, Marcello Filotico, Vincenzo Montesarchio, Maria D’Armiento, Francesco Corcione and Francesco Salvatore

Int. J. Mol. Sci. 2024, 25(5), 2716; https://doi.org/10.3390/ijms25052716 - 27 Feb 2024

Viewed by 731

Abstract

Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers. Full article

(This article belongs to the Special Issue Colorectal Cancer: A Molecular Genetics Perspective)

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