Dataset Information

Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study.

ABSTRACT: BACKGROUND:We investigated the associations between v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E, henceforth BRAF) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and colorectal cancer (CRC) prognosis, using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE39582) datasets. MATERIALS AND METHODS:The effects of BRAF and KRAS mutations on overall survival (OS) and disease-free survival (DFS) of CRC were evaluated. RESULTS:The mutational status of BRAF and KRAS genes was not associated with overall survival (OS) or DFS of the CRC patients drawn from the TCGA database. The 3-year OS and DFS rates of the BRAF mutation (+) vs. mutation (-) groups were 92.6% vs. 90.4% and 79.7% vs. 68.4%, respectively. The 3-year OS and DFS rates of the KRAS mutation (+) vs. mutation (-) groups were 90.4% vs. 90.5% and 65.3% vs. 73.5%, respectively. In stage II patients, however, the 3-year OS rate was lower in the BRAF mutation (+) group than in the mutation (-) group (85.5% vs. 97.7%, p <0.001). The mutational status of BRAF genes of 497 CRC patients drawn from the GSE39582 database was not associated with OS or DFS. The 3-year OS and DFS rates of BRAF mutation (+) vs. mutation (-) groups were 75.7% vs. 78.9% and 73.6% vs. 71.1%, respectively. However, KRAS mutational status had an effect on 3-year OS rate (71.9% mutation (+) vs. 83% mutation (-), p = 0.05) and DFS rate (66.3% mutation (+) vs. 74.6% mutation (-), p = 0.013). CONCLUSIONS:We found no consistent association between the mutational status of BRAF nor KRAS and the OS and DFS of CRC patients from the TCGA and GSE39582 databases. Studies with longer-term records and larger patient numbers may be necessary to expound the influence of BRAF and KRAS mutations on the outcomes of CRC.

SUBMITTER: Lee JH

PROVIDER: S-EPMC6351956 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study.

Lee Joon-Hyop JH Ahn Jiyoung J Park Won Seo WS Choe Eun Kyung EK Kim Eunyoung E Shin Rumi R Heo Seung Chul SC Jung Sohee S Kim Kwangsoo K Chai Young Jun YJ Chae Heejoon H

Journal of clinical medicine 20190117 1

<h4>Background</h4>We investigated the associations between v-Raf murine sarcoma viral oncogene homolog B1 (<i>BRAF</i><sup>V600E</sup>, henceforth <i>BRAF</i>) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog <i>(</i><i>KRAS</i>) mutations and colorectal cancer (CRC) prognosis, using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE39582) datasets.<h4>Materials and methods</h4>The effects of <i>BRAF</i> and <i>KRAS</i> mutations on overall survival (OS) and disease-fre ...[more]

PMID: 30658510

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Project description:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide. Regulatory T cells (Tregs) are a key constituent of immune cells in the tumor microenvironment (TME) and are significantly associated with patient outcomes. Our study aimed to construct a Treg-associated signature to predict the prognosis of CRC patients. The genes’ expression values and patients’ clinicopathological features were downloaded from TCGA and gene expression omnibus (GEO) databases. The single-cell RNA (scRNA) sequencing data of CRC were analyzed through the Deeply Integrated human Single-Cell Omics database. WGCNA analysis was used to select Tregs-associated genes (TrAGs). The infiltrated levels of immune and stromal cells were accessed through the ESTIMATE algorithm. Cox regression analysis and the LASSO algorithm were implemented to construct prognostic models. Gene set enrichment analysis (GSEA) was performed to annotate enriched gene sets. Based on scRNA sequencing data, our study uncovered that more Tregs were significantly enriched in the TME of CRC. Then we identified 123 differentially expressed TrAGs which mainly participated in immune regulation. Given that CRC patients were reclassified into 2 subgroups with distinct overall survival based on 26 differentially expressed TrAGs with prognostic values, we subsequently constructed a signature for CRC. After training and validating in independent cohorts, we proved that this prognostic model can be well applied to predict the prognosis of CRC patients. Further analysis exhibited that more tumor-suppressing immune cells and higher immune checkpoint genes were enriched in CRC patients with high-risk scores. Moreover, immunohistochemistry analysis validated that the genes in the prognostic model were significantly elevated in CRC tissues. We were the first to construct a prognostic signature for CRC based on TrAGs and further revealed that the poor prognosis of patients was mainly attributed to the tumor-suppressing microenvironment and upregulated immune checkpoint genes in tumor tissues.

Project description:BackgroundThe mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population.MethodsWe retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N?=?1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test, with significance level of 0.05.ResultsIn stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation.ConclusionsThe BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it represents a marker of much higher risk than previously considered. KRAS mutation status does not seem to represent a strong prognostic variable.

Dataset Information

Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study.

Publications

Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study.

Similar Datasets

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