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Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies
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Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies

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 (8 January 2021) | Viewed by 17415

Special Issue Editor

Dr. Yannick D. Benoit

E-Mail Website
Guest Editor
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canad
Interests: cancer; stem cells; epigenetics; digestive systems; pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer is now the second-most common cause of cancer-related deaths in most developed countries. Incidence and mortality rates have also dramatically increased in young adults over recent decades, making it a growing public health concern worldwide. The genetic diversity of colorectal cancer has been historically well appreciated, and intensive research in the field is consistently identifying new pathological determinants. However, genomic alterations are unable to solely account for the non-uniform distribution of functional attributes that can be observed within colorectal tumor heterogeneity. For instance, epigenetics and chromatin regulating mechanisms were pinpointed as key elements in the establishment of intratumoral cellular hierarchy and maintenance of cancer stem cell populations. As a result, substantial effort has been deployed to foster novel molecular tools and therapeutics, targeting pathways linked to newly uncovered genetic factors and specific compartments of tumor heterogeneity. These include, but are not limited to, selective inhibitors of chromatin editing enzymes responsible for pro-oncogenic epigenome alterations.

For this Special Issue of Genes, we welcome authors to submit reviews, new methods, commentaries, and original articles covering aspects of colon cancer genetics, epigenetics, and the development of novel therapeutic approaches. Contributions are expected to cover a broad range of topics within the scope of the journal, such as the genetic determinants of colorectal cancer, mechanisms impacting genome stability, chromatin organization, and transcriptional activity in colorectal tumorigenesis, as well as pharmacological and genome editing strategies targeting the disease. We look forward to your contributions.

Dr. Yannick D. Benoit
Guest Editor

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

  • Colon cancer
  • Genetics
  • Epigenetics
  • Colorectal tumorigenesis
  • Chromatin organization
  • Novel therapies

Published Papers (6 papers)

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17 pages, 1186 KiB  
Article
APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome
by Vittoria Disciglio, Giovanna Forte, Candida Fasano, Paola Sanese, Martina Lepore Signorile, Katia De Marco, Valentina Grossi, Filomena Cariola and Cristiano Simone
Genes 2021, 12(3), 353; https://doi.org/10.3390/genes12030353 - 28 Feb 2021
Cited by 2 | Viewed by 2797
Abstract
Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC [...] Read more.
Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature meta-analysis of APC splicing mutations. We found that 119 unique APC splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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16 pages, 1449 KiB  
Article
Detection of Somatic Mutations with ddPCR from Liquid Biopsy of Colorectal Cancer Patients
by Uršula Prosenc Zmrzljak, Rok Košir, Zoran Krivokapić, Dragica Radojković and Aleksandra Nikolić
Genes 2021, 12(2), 289; https://doi.org/10.3390/genes12020289 - 19 Feb 2021
Cited by 14 | Viewed by 3239
Abstract
Liquid biopsy and cell-free DNA (cfDNA) show great promise in cancer diagnostics. In this study, we designed a custom droplet digital PCR (ddPCR) assay for the quantification and quality control of cfDNA isolated from serum. The assay was validated on a group of [...] Read more.
Liquid biopsy and cell-free DNA (cfDNA) show great promise in cancer diagnostics. In this study, we designed a custom droplet digital PCR (ddPCR) assay for the quantification and quality control of cfDNA isolated from serum. The assay was validated on a group of locally advanced colorectal cancer (CRC) patients and two control groups—patients with hemorrhoids and healthy individuals. The assay shows a high correlation with Qubit measurement (r = 0.976) but offers a higher dynamic range. Mean concentrations of cfDNA were 12.36 ng/µL, 5.17 ng/µL, and 0.29 ng/µL for CRC, hemorrhoid patients, and healthy controls, respectively. The quality of cfDNA was assessed with the measurement of B-cell DNA contamination. On a subset of CRC patients, we compared the mutation status on KRAS (G12A, G12D, G12V, G13D) and BRAF (V600E) genes in the primary tumor and cfDNA isolated from the serum. A total of 70.6% of primary tumor samples were mutated, and the mean fractional abundance of mutations was 9.50%. The matching serum samples were mutated in 38% cases with an average fractional abundance of 0.23%. We conclude that any decisions based solely on the amount of cfDNA present in patient serum must be interpreted carefully and in the context of co-morbidities. This study explores the potential of ddPCR somatic mutations detection from liquid biopsy as a supplement to tissue biopsy in targeted personalized CRC patient management. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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12 pages, 2364 KiB  
Article
Cdx2 Regulates Intestinal EphrinB1 through the Notch Pathway
by Yalun Zhu, Alexa Hryniuk, Tanya Foley, Bradley Hess and David Lohnes
Genes 2021, 12(2), 188; https://doi.org/10.3390/genes12020188 - 28 Jan 2021
Cited by 3 | Viewed by 2197
Abstract
The majority of colorectal cancers harbor loss-of-function mutations in APC, a negative regulator of canonical Wnt signaling, leading to intestinal polyps that are predisposed to malignant progression. Comparable murine APC alleles also evoke intestinal polyps, which are typically confined to the small [...] Read more.
The majority of colorectal cancers harbor loss-of-function mutations in APC, a negative regulator of canonical Wnt signaling, leading to intestinal polyps that are predisposed to malignant progression. Comparable murine APC alleles also evoke intestinal polyps, which are typically confined to the small intestine and proximal colon, but do not progress to carcinoma in the absence of additional mutations. The Cdx transcription factors Cdx1 and Cdx2 are essential for homeostasis of the intestinal epithelium, and loss of Cdx2 has been associated with more aggressive subtypes of colorectal cancer in the human population. Consistent with this, concomitant loss of Cdx1 and Cdx2 in a murine APC mutant background leads to an increase in polyps throughout the intestinal tract. These polyps also exhibit a villous phenotype associated with the loss of EphrinB1. However, the basis for these outcomes is poorly understood. To further explore this, we modeled Cdx2 loss in SW480 colorectal cancer cells. We found that Cdx2 impacted Notch signaling in SW480 cells, and that EphrinB1 is a Notch target gene. As EphrinB1 loss also leads to a villus tumor phenotype, these findings evoke a mechanism by which Cdx2 impacts colorectal cancer via Notch-dependent EphrinB1 signaling. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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15 pages, 4603 KiB  
Article
A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
by Gašper Klančar, Ana Blatnik, Vita Šetrajčič Dragoš, Vesna Vogrič, Vida Stegel, Olga Blatnik, Primož Drev, Barbara Gazič, Mateja Krajc and Srdjan Novaković
Genes 2020, 11(3), 325; https://doi.org/10.3390/genes11030325 - 18 Mar 2020
Cited by 8 | Viewed by 3053
Abstract
The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the [...] Read more.
The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel MLH1 in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in MLH1. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel MLH1 variant as likely pathogenic, we confirmed the LS in this family. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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6 pages, 592 KiB  
Commentary
Intestinal Microbiota Influences DNA Methylome and Susceptibility to Colorectal Cancer
by Aïcha Zouggar, Joshua R. Haebe and Yannick D. Benoit
Genes 2020, 11(7), 808; https://doi.org/10.3390/genes11070808 - 16 Jul 2020
Cited by 13 | Viewed by 3152
Abstract
In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response [...] Read more.
In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response and colorectal cancer. Here, we discuss the impact of such a discovery on the understanding of how the intestinal microbiota may contribute to epigenetic reprogramming and influence the onset of colorectal tumorigenesis. Finally, we examine the prospect of TET inhibition strategies as a therapeutic and/or preventive approach for colorectal cancer in patients afflicted by inflammatory bowel disease. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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5 pages, 615 KiB  
Perspective
G9a Is SETting the Stage for Colorectal Oncogenesis
by Christopher J. Bergin and Yannick D. Benoit
Genes 2020, 11(6), 616; https://doi.org/10.3390/genes11060616 - 04 Jun 2020
Cited by 3 | Viewed by 2369
Abstract
Recently, Kato et al. reported recurrent activating mutations in the SET domain of histone methyltransferase G9a, driving an oncogenic cascade in melanoma. The authors also reported correlations between G9a expression and the regulation of the canonical WNT pathway. Although we could not observe [...] Read more.
Recently, Kato et al. reported recurrent activating mutations in the SET domain of histone methyltransferase G9a, driving an oncogenic cascade in melanoma. The authors also reported correlations between G9a expression and the regulation of the canonical WNT pathway. Although we could not observe such mutations in human colorectal adenocarcinoma, newly reported findings are of high relevance to colorectal cancer, as WNT target gene signatures were closely associated with G9a expression. Here, we put into perspective such new results on G9a expression in colorectal cancers and the potential relationship with tumor heterogeneity and acquisition of neoplastic stemness. Full article
(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)
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