Dataset Information

Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers.

ABSTRACT:

Background

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and its development is associated with the gains and/or losses of genetic material, which leads to the emergence of main driver genes with higher mutational frequency. In addition, there are other genes with mutations that have weak tumor-promoting effects, known as mini-drivers, which could aggravate the development of oncogenesis when they occur together. The aim of our work was to use computer analysis to explore the survival impact, frequency, and incidence of mutations of possible mini-driver genes to be used for the prognosis of CRC.

Methods

We retrieved data from three sources of CRC samples using the cBioPortal platform and analyzed the mutational frequency to exclude genes with driver features and those mutated in less than 5% of the original cohort. We also observed that the mutational profile of these mini-driver candidates is associated with variations in the expression levels. The candidate genes obtained were subjected to Kaplan-Meier curve analysis, making a comparison between mutated and wild-type samples for each gene using a p-value threshold of 0.01.

Results

After gene filtering by mutational frequency, we obtained 159 genes of which 60 were associated with a high accumulation of total somatic mutations with Log₂ (fold change) > 2 and p values < 10^-5. In addition, these genes were enriched to oncogenic pathways such as epithelium-mesenchymal transition, hsa-miR-218-5p downregulation, and extracellular matrix organization. Our analysis identified five genes with possible implications as mini-drivers: DOCK3, FN1, PAPPA2, DNAH11, and FBN2. Furthermore, we evaluated a combined classification where CRC patients with at least one mutation in any of these genes were separated from the main cohort obtaining a p-value < 0.001 in the evaluation of CRC prognosis.

Conclusion

Our study suggests that the identification and incorporation of mini-driver genes in addition to known driver genes could enhance the accuracy of prognostic biomarkers for CRC.

SUBMITTER: Campos Segura AV

PROVIDER: S-EPMC10198153 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers.

Campos Segura Anthony Vladimir AV Velásquez Sotomayor Mariana Belén MB Gutiérrez Román Ana Isabel Flor AIF Ortiz Rojas César Alexander CA Murillo Carrasco Alexis Germán AG

PeerJ 20230516

<h4>Background</h4>Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and its development is associated with the gains and/or losses of genetic material, which leads to the emergence of main driver genes with higher mutational frequency. In addition, there are other genes with mutations that have weak tumor-promoting effects, known as mini-drivers, which could aggravate the development of oncogenesis when they occur together. The aim of our work was to use computer ana ...[more]

PMID: 37214090

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Project description:Colorectal cancer (CRC) remains as one of the most common cause of worldwide cancer morbidity and mortality. Improvements in surgical modalities and adjuvant chemotherapy have increased the cure rates in early stage disease, but a significant portion of the patients will develop recurrence or advanced disease. The efficacy of chemotherapy of recurrence and advanced CRC has improved significantly over the last decade. Previously, the historical drug 5-fluorouracil was used as single chemotherapeutic agent. Now with the addition of other drugs such as capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, vemurafenib, and dabrafenib, the median survival of patients with advanced CRC has significantly improved from less than a year to the current standard of almost 2 years. However, the side effects of systemic therapy such as toxicity may cause fatal complications and have a major consequences on the patients' quality of life. Hence, there is an urgent need for key biomarkers which will enable the selection of optimal drug singly or in combination for an individual patient. The application of personalized therapy based on DNA testing could aid the clinicians in providing the most effective chemotherapy agents and dose modifications for each patient. Yet, some of the current findings are controversial and the evidences are conflicting. This review aims at summarizing the current state of knowledge about germline pharmacogenomics DNA variants that are currently used to guide therapeutic decisions and variants that have the potential to be clinically useful in the future. In addition, current updates on germline variants conferring treatment sensitivity, drug resistance to existing chemotherapy agents and variants affecting prognosis and survival will also be emphasized. Different alteration in the same gene might confer resistance or enhanced sensitivity; and while most of other published reviews generally stated only the gene name and codon location, we will specifically discuss the exact variants to offer more accurate information in this mini review.

Project description:BackgroundInflammation-related biomarkers, such as systemic inflammation score (SIS) and neutrophil-lymphocyte ratio (NLR), are associated with colorectal cancer prognosis. However, the combined role of SIS, NLR, and clinicopathological factors in stage II/III colorectal cancer remains unclear. This study developed a nomogram to predict long-term prognosis for these patients.MethodsThis retrospective study included 1540 patients (training set) from the First Affiliated Hospital of Kunming Medical University and 152 patients (testing set) from The Honghe Third People's Hospital. Cox regression identified independent prognostic factors, and machine learning established predictive models. Model performance was evaluated by the C-index, area under the curve (AUC), and decision curve analysis (DCA).ResultsIn the training set, a total of 1540 patients with stage II/III colorectal cancer were included. More than 70 years old (HR = 1.830, p = 0.000); SIS = 2 (HR = 1.693, p = 0.002); Preoperative CEA more than 5 ng/mL (HR = 1.614, p = 0.000); and Moderately differentiated (HR = 1.438, p = 0.011); or Low/undifferentiated (HR = 2.126, p = 0.000); The pN1 (HR = 2.040, p = 0.000) and pN2 (HR = 3.297, p = 0.000) stages were considered independent prognostic risk factors of stage II/III colorectal cancer. Negative perineural invasion (HR = 0.733, p = 0.014) and NLR less than 4 (HR = 0.696, p = 0.022) were considered independent prognostic protective factors of stage II/III colorectal cancer. A nomogram was established based on SIS, NLR, and the clinicopathological results for predicting and validating the overall survival in the training and testing sets. The C-index of the training set was 0.746, and the C-index of the testing set was 0.708, indicating the high prediction efficiency of the nomogram.ConclusionsA nomogram combining SIS, NLR, and clinicopathological factors provides an effective, cost-efficient tool for predicting the prognosis of stage II/III colorectal cancer. Future studies will validate its long-term predictive performance in larger, multicenter cohorts.

Dataset Information

Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers.

Background

Methods

Results

Conclusion

Publications

Impact of mini-driver genes in the prognosis and tumor features of colorectal cancer samples: a novel perspective to support current biomarkers.

Similar Datasets

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