Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review)

Ahmad, Rehan; Singh, Jaikee Kumar; Wunnava, Amoolya; Al‐Obeed, Omar; Abdulla, Maha; Srivastava, Sandeep

doi:10.3892/ijmm.2021.4847

Cited by 82 publications

(52 citation statements)

References 274 publications

(272 reference statements)

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“…Regarding genomic alterations of the Myc pathway, MYC was the only altered gene and identified in 10.2% of CRC tissues ( Figure 3 D). A TGF-β signaling pathway is involved in CRC progression through invasion and metastasis promotion of cancer cells [ 8 ]. In the present study, the TGF-β pathway alteration frequency was 26%, including SMAD4 and SMAD2 mutations in 22.7% and 2.3% samples, respectively ( Figure 2 B and Figure 3 E).…”

Section: Resultsmentioning

confidence: 99%

“…CRC is a group of heterogenous diseases with diverse genomic features and corresponding treatment responses [ 7 , 8 ]. For example, anti-epidermal growth factor receptor (EGFR) antibodies combined with BRAF inhibitors are indicated for BRAF -mutated mCRC treatment; however, patients with mCRC harboring RAS mutation have a poor response to EGFR-targeting treatments [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer

Huang

Lin

et al. 2021

Diagnostics

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Systemic characterization of genomic alterations into signaling pathways helps to understand the molecular pathogenies of colorectal cancer; however, their clinical implications remain unclear. Here, 128 patients with metastatic colorectal cancer (mCRC) receiving targeted next generation sequencing were retrospectively enrolled to analyze the impact of altered oncogenic pathways on clinical outcome. The datasets from Memorial Sloan Kettering Cancer Center were used for validation. In 123 patients with non-MSI-high tumor, the most common mutated gene was TP53 (84.6%), followed by APC (78.0%), KRAS (49.6%), and SMAD4 (22.8%). When mutated genes were allocated into signaling pathways defined as The Cancer Genome Atlas Pan-Cancer Analysis Project, alterations of cell cycle, Wnt, p53, RTK-RAS, PI3K, TGF-β, Notch, and Myc pathways were identified in 88%, 87%, 85%, 75%, 28%, 26%, 17%, and 10% of mCRC tissues, respectively. The survival analyses revealed that Myc and TGF-β pathway alterations were associated with a shorter overall survival (OS) (hazard ratio [HR]: 2.412; 95% confidence interval [CI]: 1.139–5.109; p = 0.018 and HR: 2.754; 95% CI: 1.044–7.265; p = 0.033, respectively). The negative prognostic impact of altered TGF-β pathway was maintained in patients receiving an anti-EGFR antibody. The OS of patients with mCRC carrying MYC and BRAF mutation was shorter than those with either MYC or BRAF mutation (HR: 4.981, 95% CI: 0.296–83.92; p = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer

Huang

Lin

et al. 2021

Diagnostics

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“…Why for chromosome 18, being one of the three most common viable human trisomies [ 2 ], hardly never UPD-cases are reported must be elucidated in future studies. Still, there are tumor related genes on this chromosome, especially tumorsuppressor genes, which could play a role in early embryogenesis the one or other way [ 28 ]. Isodisomy, heterodisomy, mixed iso/heterodisomy, segmental UPD The different possible consequences of the isodisomy (including segmental UPD), heterodisomy and mixed iso/heterodisomy were treated already above.…”

Section: Discussionmentioning

confidence: 99%

Uniparental disomy is a chromosomic disorder in the first place

Liehr

2022

Mol Cytogenet

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Background Uniparental disomy (UPD) is well-known to be closely intermingled with imprinting disorders. Besides, UPD can lead to a disease by ‘activation’ of a recessive gene mutation or due to incomplete (cryptic) trisomic rescue. Corresponding to all common theories how UPD forms, it takes place as a consequence of a “chromosomic problem”, like an aneuploidy or a chromosomal rearrangement. Nonetheless, UPD is rarely considered as a cytogenetic, but most often as a molecular genetic problem. Results Here a review on the ~ 4900 published UPD-cases is provided, and even though being biased as discussed in the paper, the following insights have been given from that analysis: (1) the rate of maternal to paternal UPD is 2~3 to 1; (2) at most only ~ 0.03% of the available UPD cases are grasped scientifically, yet; (3) frequencies of single whole-chromosome UPDs are non-random, with UPD(16) and UPD(15) being most frequent in clinically healthy and diseased people, respectively; (4) there is a direct correlation of UPD frequency and known frequent first trimester trisomies, except for chromosomes 1, 5, 11 and 18 (which can be explained); (5) heterodisomy is under- and UPD-mosaicism is over-represented in recent reports; and (6) cytogenetics is not considered enough when a UPD is identified. Conclusions As UPD is diagnosed using molecular genetic approaches, and thus by specialists considering chromosomes at best as a whim of nature, most UPD reports lack the chromosomal aspect. Here it is affirmed and substantiated by corresponding data that UPD is a chromosomic disorder in the first place and cytogenetic analyses is indicated in each diagnosed UPD-case.

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“…While for diseases with known underlying mechanism or targeted therapy, the selection of subjects can be straightforward to obtain high efficacy of a given intervention, this cannot be achieved, unfortunately, in the case of CRC. It is a multifactorial disease, with unknown or partially elucidated mechanisms, sometimes including host factors, local environmental factors, lifestyle factors (35), microbiome, and host diets that have been extensively studied. All of these play a causal and protective role in the development of CRC (36).…”

Section: Introductionmentioning

confidence: 99%

Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients’ Stratification

et al. 2022

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In order to ensure that primary endpoints of clinical studies are attained, the patients’ stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients’ stratification—mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts’ diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients’ stratification towards a personalized approach of early diagnosis and treatment.

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Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review)

Cited by 82 publications

References 274 publications

Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer

Association between Altered Oncogenic Signaling Pathways and Overall Survival of Patients with Metastatic Colorectal Cancer

Uniparental disomy is a chromosomic disorder in the first place

Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients’ Stratification

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