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Molecular Biomarkers in Colorectal Adenocarcinoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 39264

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Special Issue Editors

Dr. Christos K. Kontos

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Guest Editor

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens, Greece
Interests: colorectal cancer; leukemia; tumor biomarkers; circular RNA; tRNA fragments; transcriptomics; anticancer drugs; apoptosis; BCL2 family; alternative splicing.
Special Issues, Collections and Topics in MDPI journals

Dr. Pinelopi I. Artemaki

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Guest Editor

Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
Interests: alternative splicing; RNA biology; circular RNAs; pre-mRNAs; post-transcriptional analysis; apoptosis; BCL2 family; colorectal adenocarcinoma; molecular biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is considered the third most fatal type of cancer in both men and women globally. In recent years, great progress has been achieved towards the understanding of the molecular basis of CRC, and therefore, a new era in diagnosis, prognosis, and therapeutic approaches has emerged. Despite this improvement, however, there is an imperative need for new molecular biomarkers in CRC, since this malignancy is very heterogeneous. Moreover, RNA molecules including microRNAs, RNA-derived fragments (e.g., tRNA-derived RNA fragments, tRFs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) constitute a hot research topic. In this perspective, it would be interesting if such newly characterized biomolecules as well as components of classical signaling pathways, such as the EGFR/KRAS/MAPK and the PI3K/AKT1/mTOR pathways, were further assessed for their potential value as molecular CRC biomarkers and/or therapeutic targets.

This Special Issue focuses on novel molecular biomarkers in CRC and general approaches which will contribute to further elucidation of the underlying molecular mechanisms. Authors are encouraged to submit their research studies concerning this topic. All studies will be taken into consideration. The Guest Editors are willing to also evaluate manuscripts describing other aspects of CRC pathobiology proposed by the authors. We hope that this Special Issue regarding molecular biomarkers of colorectal cancer will rouse the interest of the readers of this journal.

Assistant Prof. Christos K. Kontos
Dr. Pinelopi I. Artemaki
Guest Editors

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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

colorectal adenocarcinoma
cancer pathobiology
molecular biomarkers
diagnosis and prognosis
prediction of therapy selection
therapeutic targets
RNA molecules
microRNA
long noncoding RNA
circular RNA

Published Papers (14 papers)

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Editorial

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5 pages, 182 KiB

Open AccessEditorial

Editorial for the Special Issue “Molecular Biomarkers in Colorectal Adenocarcinoma”

by Pinelopi I. Artemaki and Christos K. Kontos

Int. J. Mol. Sci. 2021, 22(4), 2052; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042052 - 19 Feb 2021

Cited by 4 | Viewed by 1369

Abstract

Colorectal cancer (CRC) is one of the most common malignancies, with an elevated mortality rate [...] Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

Research

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17 pages, 4043 KiB

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Identification of Two Novel Circular RNAs Deriving from BCL2L12 and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer

by Paraskevi Karousi, Pinelopi I. Artemaki, Christina D. Sotiropoulou, Spyridon Christodoulou, Andreas Scorilas and Christos K. Kontos

Int. J. Mol. Sci. 2020, 21(22), 8867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228867 - 23 Nov 2020

Cited by 24 | Viewed by 3513

Abstract

The utility of circular RNAs (circRNAs) as molecular biomarkers has recently emerged. However, only a handful of them have already been studied in colorectal cancer (CRC). The purpose of this study was to identify new circRNAs deriving from BCL2L12, a member of the BCL2 apoptosis-related family, and investigate their potential as biomarkers in CRC. Total RNA extracts from CRC cell lines and tissue samples were reversely transcribed. By combining PCR with divergent primers and nested PCR followed by Sanger sequencing, we were able to discover two BCL2L12 circRNAs. Subsequently, bioinformatical tools were used to predict the interactions of these circRNAs with microRNAs (miRNAs) and RNA-binding proteins (RBPs). Following a PCR-based pre-amplification, real-time qPCR was carried out for the quantification of each circRNA in CRC samples and cell lines. Biostatistical analysis was used to assess their potential prognostic value in CRC. Both novel BCL2L12 circRNAs likely interact with particular miRNAs and RBPs. Interestingly, circ-BCL2L12-2 expression is inversely associated with TNM stage, while circ-BCL2L12-1 overexpression is associated with shorter overall survival in CRC, particularly among TNM stage II patients. Overall, we identified two novel BCL2L12 circRNAs, one of which can further stratify TNM stage II patients into two subgroups with substantially distinct prognosis. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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29 pages, 3101 KiB

Open AccessArticle

Revised Exon Structure of l-DOPA Decarboxylase (DDC) Reveals Novel Splice Variants Associated with Colorectal Cancer Progression

by Pinelopi I. Artemaki, Maria Papatsirou, Michaela A. Boti, Panagiotis G. Adamopoulos, Spyridon Christodoulou, Dido Vassilacopoulou, Andreas Scorilas and Christos K. Kontos

Int. J. Mol. Sci. 2020, 21(22), 8568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228568 - 13 Nov 2020

Cited by 9 | Viewed by 2077

Abstract

Colorectal cancer (CRC) is a highly heterogenous malignancy with an increased mortality rate. Aberrant splicing is a typical characteristic of CRC, and several studies support the prognostic value of particular transcripts in this malignancy. l-DOPA decarboxylase (DDC) and its derivative neurotransmitters play a multifaceted role in physiological and pathological states. Our recent data support the existence of 6 DDC novel exons. In this study, we investigated the existence of additional DDC novel exons and transcripts, and their potential value as biomarkers in CRC. Next-generation sequencing (NGS) in 55 human cell lines coupled with Sanger sequencing uncovered 3 additional DDC novel exons and 20 splice variants, 7 of which likely encode new protein isoforms. Eight of these transcripts were detected in CRC. An in-house qPCR assay was developed and performed in TNM II and III CRC samples for the quantification of transcripts bearing novel exons. Extensive biostatistical analysis uncovered the prognostic value of specific DDC novel exons for patients’ disease-free and overall survival. The revised DDC exon structure, the putative protein isoforms with distinct functions, and the prognostic value of novel exons highlight the pivotal role of DDC in CRC progression, indicating its potential utility as a molecular biomarker in CRC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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13 pages, 2267 KiB

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Genotype-Based Gene Expression in Colon Tissue—Prediction Accuracy and Relationship with the Prognosis of Colorectal Cancer Patients

by Heike Deutelmoser, Justo Lorenzo Bermejo, Axel Benner, Korbinian Weigl, Hanla A. Park, Mariam Haffa, Esther Herpel, Martin Schneider, Cornelia M. Ulrich, Michael Hoffmeister, Jenny Chang-Claude, Hermann Brenner and Dominique Scherer

Int. J. Mol. Sci. 2020, 21(21), 8150; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218150 - 31 Oct 2020

Cited by 4 | Viewed by 2247

Abstract

Colorectal cancer (CRC) survival has environmental and inherited components. The expression of specific genes can be inferred based on individual genotypes—so called expression quantitative trait loci. In this study, we used the PrediXcan method to predict gene expression in normal colon tissue using individual genotype data from 91 CRC patients and examined the correlation ρ between predicted and measured gene expression levels. Out of 5434 predicted genes, 58% showed a negative ρ value and only 16% presented a ρ higher than 0.10. We subsequently investigated the association between genotype-based gene expression in colon tissue for genes with ρ > 0.10 and survival of 4436 CRC patients. We identified an inverse association between the predicted expression of ARID3B and CRC-specific survival for patients with a body mass index greater than or equal to 30 kg/m² (HR (hazard ratio) = 0.66 for an expression higher vs. lower than the median, p = 0.005). This association was validated using genotype and clinical data from the UK Biobank (HR = 0.74, p = 0.04). In addition to the identification of ARID3B expression in normal colon tissue as a candidate prognostic biomarker for obese CRC patients, our study illustrates the challenges of genotype-based prediction of gene expression, and the advantage of reassessing the prediction accuracy in a subset of the study population using measured gene expression data. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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13 pages, 2328 KiB

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Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma

by Faysal Bin Hamid, Vinod Gopalan, Marco Matos, Cu-Tai Lu and Alfred King-yin Lam

Int. J. Mol. Sci. 2020, 21(20), 7766; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207766 - 20 Oct 2020

Cited by 5 | Viewed by 2541

Abstract

The aim of the present study was to isolate and investigate the genetic heterogeneities in single circulating tumour cells (CTCs) from patients with colorectal carcinoma (CRC). Twenty-eight single CTCs were collected from eight patients with CRC using a negative immunomagnetic enrichment method. After validation with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in 3 colon cancer cell lines, a panel of 19 genes were used to analyse the single CTCs (n = 28), primary colorectal carcinoma tissues (n = 8) and colon carcinoma cells (n = 6) using real-time qPCR. Genetic heterogeneities were assessed by comparing gene expression profiles of single CTCs from the different patients and in the same patient, respectively. Genetic profiling of the single CTCs showed extensive heterogeneities of the selected genes among the CTCs. Hierarchical clustering analyses exhibited two clusters of CTCs with differentially expressed genes, which highlighted different modifications from the primary carcinomas. Further, the genetic heterogeneities were observed between different patients or in the same patient. Finally, AKT1 expression was significantly (p = 0.0129) higher in single CTCs from CRC of advanced pathological stages (III or IV) CRC than in CTCs from CRC of early stages (I or II). Our findings suggest that single-cell genetic analysis can monitor the genetic heterogeneities and guide the personalised therapeutic targets in clinical sectors. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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13 pages, 2342 KiB

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PD-L1 Expression on Circulating Tumour Cells May Be Predictive of Response to Regorafenib in Patients Diagnosed with Chemorefractory Metastatic Colorectal Cancer

by Lucrezia Raimondi, Filippo Maria Raimondi, Laura Di Benedetto, Giuseppe Cimino and Gian Paolo Spinelli

Int. J. Mol. Sci. 2020, 21(18), 6907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186907 - 20 Sep 2020

Cited by 13 | Viewed by 2420

Abstract

Regorafenib, targeting a broad range of receptor tyrosine kinases (RTKs), is an oral multikinase inhibitor which improves the progression-free survival (PFS) and overall survival (OS) of patients diagnosed with chemorefractory metastatic colorectal cancer (mCRC), making an immunosuppressive tumour microenvironment. The correlation between PD-1/PD-L1 expression and RTKs inhibition has been studied in several tumour types but has not been analyzed extensively in mCRC in the era of regorafenib. In this study, using liquid biopsy, we evaluated the opportunity to reveal if PD-L1 expression on circulating tumour cells (CTCs) could serve as a predictive biomarker of response and clinical benefit in patients treated with regorafenib as the third line of treatment. We analyzed a cohort of forty chemorefractory metastatic colorectal cancer patients, of whom twenty-six KRAS mutated, treated with regorafenib, all as the third line of treatment. Blood samples were collected from patients prior to treatment and longitudinally four and eight weeks after initiation of therapy. CTCs were identified using multiparametric flow cytometry; therefore, PD-L1 expression was evaluated. Objective responses were defined following the RECIST criteria v.1.1. Moreover, focusing on peripheral blood biomarkers, we found that high platelet-to-lymphocyte ratio (PLR) was an independent prognostic indicator of poor OS. For the first time, our study showed the usefulness of sequential assessments of CTCs as a non-invasive real-time biopsy to evaluate PD-L1 expression in patients diagnosed with mCRC and treated with regorafenib. Our analysis suggests that by assessing PD-L1 expression on CTCs, we could predict who will benefit from regorafenib, offering highly individualized treatment plans. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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15 pages, 279 KiB

Open AccessArticle

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients

by Dominique Scherer, Heike Deutelmoser, Yesilda Balavarca, Reka Toth, Nina Habermann, Katharina Buck, Elisabeth Johanna Kap, Akke Botma, Petra Seibold, Lina Jansen, Justo Lorenzo Bermejo, Korbinian Weigl, Axel Benner, Michael Hoffmeister, Alexis Ulrich, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude and Cornelia M. Ulrich

Int. J. Mol. Sci. 2020, 21(15), 5395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155395 - 29 Jul 2020

Cited by 14 | Viewed by 2367

Abstract

An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

13 pages, 1232 KiB

Open AccessArticle

ABCG2 Protein Levels and Association to Response to First-Line Irinotecan-Based Therapy for Patients with Metastatic Colorectal Cancer

by Jesper Andreas Palshof, Camilla Natasha Cederbye, Estrid Vilma Solyom Høgdall, Tim Svenstrup Poulsen, Dorte Linnemann, Sune Boris Nygaard, Jan Stenvang, Ib Jarle Christensen, Benny Vittrup Jensen, Per Pfeiffer, Nils Brünner, Mette Yilmaz, Birgitte Martine Viuff and Dorte Lisbet Nielsen

Int. J. Mol. Sci. 2020, 21(14), 5027; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145027 - 16 Jul 2020

Cited by 7 | Viewed by 2415

Abstract

In this study we investigated the use of cancer cell protein expression of ABCG2 to predict efficacy of systemic first-line irinotecan containing therapy in patients with metastatic colorectal cancer (mCRC). From a Danish national cohort, we identified 119 mCRC patients treated with irinotecan containing therapy in first-line setting. Among these, 108 were eligible for analyses. Immunohistochemistry (IHC) analyses were performed on the primary tumor tissue in order to classify samples as high or low presence of ABCG2 protein. Data were then associated with patient outcome (objective response (OR), progression free survival (PFS) and overall survival (OS)). ABCG2 protein expression in the basolateral membrane was high (score 3+) in 33% of the patients. Exploratory analyses revealed a significant interaction between ABCG2 score, adjuvant treatment and OR (p = 0.041) in the 101 patients with evaluable disease. Patients with low ABCG2 (score 0–2) and no prior adjuvant therapy had a significantly higher odds ratio of 5.6 (Confidence Interval (CI) 1.68–18.7; p = 0.005) for obtaining OR. In contrast, no significant associations between ABCG2 expression and PFS or OS were found. These results suggest that measurement of the ABCG2 drug efflux pump might be used to select patients with mCRC for irinotecan treatment. However, additional studies are warranted before conclusions regarding a clinical use can be made. Moreover, patients with high ABCG2 immunoreactivity could be candidates for specific ABCG2 inhibition treatment in combination with irinotecan. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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16 pages, 3933 KiB

Open AccessArticle

Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/Polyps with Dysplasia

by Rina Fujiwara-Tani, Kiyomu Fujii, Shiori Mori, Shingo Kishi, Takamitsu Sasaki, Hitoshi Ohmori, Chie Nakashima, Isao Kawahara, Yukiko Nishiguchi, Takuya Mori, Masayuki Sho, Masuo Kondoh, Yi Luo and Hiroki Kuniyasu

Int. J. Mol. Sci. 2020, 21(11), 3840; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113840 - 28 May 2020

Cited by 20 | Viewed by 2868

Abstract

Sessile serrated adenoma/polyp with dysplasia (SSA/P-D) is an SSA/P with cellular dysplasia and has a higher risk of progressing to colon carcinogenesis. Previously, we reported that tight junction impairment by Clostridium perfringens enterotoxin (CPE) leads to activation of the transcriptional co-activator yes-associated protein (YAP) in oral squamous cell carcinoma. Here, we investigated whether CPE activates YAP to promote the malignant progression of SSA/P. E-cadherin expression was lower in the 12 cases with SSA/P-D examined than that in normal mucosa, SSA/P, or tubular adenoma (TA). Furthermore, intracellular translocation of claudin-4 (CLDN4) and nuclear translocation of YAP were observed. The CPE gene was detected in DNA extracted from SSA/P-D lesions, but not in SSA/P or TA. Treatment of the rat intestinal epithelial cell line IEC6 with low-dose CPE resulted in intracellular translocation of CLDN4 to the cytoplasmic membrane. Cytoplasmic CLDN4 showed co-precipitation with transcriptional co-activator with PDZ-binding motif, zonula occludens (ZO)-1, large tumor suppressor, and mammalian Ste20-like. Additionally, YAP co-precipitated with ZO-2 under CPE treatment led to decreased YAP phosphorylation and nuclear translocation. YAP activation promoted increase in nuclear TEA domain family member level, expression of cyclin D1, snail, vimentin, CD44, NS and decrease in E-cadherin levels, thereby inducing stemness and epithelial-mesenchymal-transition (EMT). The Hippo complex with the incorporation of CLDN4 increased stability. Upon low-dose CPE treatment, HT29 cells with BRAF^V600E gene mutation showed increased growth, enhanced invasive potential, stemness, and induced EMT phenotype, whereas HCT116 cells, which carry KRAS^G13D gene mutation, did not show such changes. In an examination of 10 colorectal cancers, an increase in EMT and stemness was observed in CPE (+) and BRAF mutation (+) cases. These findings suggest that C. perfringens might enhance the malignant transformation of SSA/P-D via YAP activation. Our findings further highlight the importance of controlling intestinal flora using probiotics or antibiotics. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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Review

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18 pages, 775 KiB

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Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer

by Luigi Laghi, Francesca Negri, Federica Gaiani, Tommaso Cavalleri, Fabio Grizzi, Gian Luigi de’ Angelis and Alberto Malesci

Int. J. Mol. Sci. 2020, 21(24), 9680; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249680 - 18 Dec 2020

Cited by 16 | Viewed by 3072

Abstract

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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21 pages, 2295 KiB

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The Role of BRAF in Metastatic Colorectal Carcinoma–Past, Present, and Future

by Angela Djanani, Silvia Eller, Dietmar Öfner, Jakob Troppmair and Manuel Maglione

Int. J. Mol. Sci. 2020, 21(23), 9001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239001 - 26 Nov 2020

Cited by 9 | Viewed by 3299

Abstract

With a global incidence of 1.8 million cases, colorectal cancer represents one of the most common cancers worldwide. Despite impressive improvements in treatment efficacy through cytotoxic and biological agents, the cancer-related death burden of metastatic colorectal cancer (mCRC) is still high. mCRC is not a genetically homogenous disease and various mutations influence disease development. Up to 12% of mCRC patients harbor mutations of the signal transduction molecule BRAF, the most prominent being BRAF^V600E. In mCRC, BRAF^V600E mutation is a well-known negative prognostic factor, and is associated with a dismal prognosis. The currently approved treatments for BRAF-mutated mCRC patients are of little impact, and there is no treatment option superior to others. However, the gradual molecular understanding over the last decades of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, resulted in the development of new therapeutic strategies targeting the involved molecules. Recently published and ongoing studies administering a combination of different inhibitors (e.g., BRAF, MEK, and EGFR) showed promising results and represent the new standard of care. In this review, we present, both, the molecular and clinical aspects of BRAF-mutated mCRC patients, and provide an update on the current and future treatment approaches that might direct the therapy of mCRC in a new era. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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20 pages, 711 KiB

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Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

by Iris B. A. W. te Paske, Marjolijn J. L. Ligtenberg, Nicoline Hoogerbrugge and Richarda M. de Voer

Int. J. Mol. Sci. 2020, 21(22), 8757; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228757 - 19 Nov 2020

Cited by 7 | Viewed by 2926

Abstract

To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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29 pages, 2068 KiB

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Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma

by Wolfgang Eberhardt, Kristina Haeussler, Usman Nasrullah and Josef Pfeilschifter

Int. J. Mol. Sci. 2020, 21(20), 7532; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207532 - 13 Oct 2020

Cited by 20 | Viewed by 3310

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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24 pages, 608 KiB

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Distant Metastasis in Colorectal Cancer Patients—Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review

by Stanislav Filip, Veronika Vymetalkova, Jiri Petera, Ludmila Vodickova, Ondrej Kubecek, Stanislav John, Filip Cecka, Marketa Krupova, Monika Manethova, Klara Cervena and Pavel Vodicka

Int. J. Mol. Sci. 2020, 21(15), 5255; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155255 - 24 Jul 2020

Cited by 37 | Viewed by 4044

Abstract

Colorectal cancer (CRC) remains a serious health problem worldwide. Approximately half of patients will develop distant metastasis after CRC resection, usually with very poor prognosis afterwards. Because patient performance after distant metastasis surgery remains very heterogeneous, ranging from death within 2 years to a long-term cure, there is a clinical need for a precise risk stratification of patients to aid pre- and post-operative decisions. Furthermore, around 20% of identified CRC cases are at IV stage disease, known as a metastatic CRC (mCRC). In this review, we overview possible molecular and clinicopathological biomarkers that may provide prognostic and predictive information for patients with distant metastasis. These may comprise sidedness of the tumor, molecular profile and epigenetic characteristics of the primary tumor and arising metastatic CRC, and early markers reflecting cancer cell resistance in mCRC and biomarkers identified from transcriptome. This review discusses current stage in employment of these biomarkers in clinical practice as well as summarizes current experience in identifying predictive biomarkers in mCRC treatment. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Adenocarcinoma)

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