Dataset Information

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

ABSTRACT: Background:Early identification of colorectal cancer (CRC) patients that are BRAF-V600E mutant and/or microsatellite instability-high (MSI-High), has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests, i.e., carbohydrate cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients from other molecular subsets of CRC. Methods:All patients with metastatic CRC from December 2016 to February 2019 were identified, and included in the study if they had both CA19-9 and CEA tests available. Circulating tumor DNA (ctDNA) testing and tissue genetic testing results were used to categorize patients into BRAF V600E microsatellite stable (MSS), MSI-High, RAS mutant MSS and RAS/RAF wild type CRCs. Kruskal-Wallis test was used to compare the CA19-9/CEA ratio between mutation types and the pairwise p values were adjusted for multiple comparisons with Holm method. For sensitivity analysis, the same analysis was repeated for the mean and median ratio of each patient. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results:BRAF-V600E MSS CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. Patients in the BRAF V600E MSS subset had the highest median CA19-9/CEA ratio versus the least median ratio in MSI-High patients. The median of maximum CA-19-9/CEA ratio was 28.92 (range, 2.76-707.27) in BRAF-V600E MSS patients and 4.06 (range, 0.46-166.74) in MSI-High subset of patients. Conclusions:To date, this is the first report utilizing the ratio of tumor markers CA19-9/CEA as a predictive rather than just prognostic tool to identify BRAF-V600E MSS and MSI-High CRC patients.

SUBMITTER: Kasi PM

PROVIDER: S-EPMC7212105 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

Kasi Pashtoon Murtaza PM Kamatham Saivaishnavi S Shahjehan Faisal F Li Zhuo Z Johnson Patrick W PW Merchea Amit A Colibaseanu Dorin T DT

Journal of gastrointestinal oncology 20200401 2

<h4>Background</h4>Early identification of colorectal cancer (CRC) patients that are BRAF-V600E mutant and/or microsatellite instability-high (MSI-High), has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests, i.e., carbohydrate cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients from other molecular subsets ...[more]

PMID: 32399264

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Project description:The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a poor patient prognosis, whereas BRAF mutant microsatellite-unstable (MSI) colorectal cancers have an excellent prognosis. BRAF wild type cancers are typically MSS and display chromosomal instability (CIN). CIN has not been extensively studied on a genome-wide basis in relation to BRAF mutational status in colorectal cancer. BRAF mutant/MSS (BRAFmut/MSS) cancers (n = 33) and BRAF mutant/MSI (BRAFmut/MSI) cancers (n = 30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with BRAF wild type/MSS (BRAFwt/MSS) cancers (n = 18) using Illumina CytoSNP-12 arrays. BRAFmut/MSS and BRAFwt/MSS cancers showed comparable numbers of CNAs/cancer at 32.8 and 29.8 respectively. However, there were differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having significantly greater proportions of focal CNAs compared to BRAFwt/MSS cancers (p<0.0001); whereas whole chromosomal arm CNAs were more common in BRAFwt/MSS cancers (p<0.0001). This related to a reduced average CNA length in BRAFmut/MSS compared to BRAFwt/MSS cancers (20.7 Mb vs 33.4 Mb;p<0.0001); and a smaller average percent of CIN affected genomes in BRAFmut/MSS compared to BRAFwt/MSS cancers (23.9% vs 34.9% respectively). BRAFmut/MSI cancers were confirmed to have low CNA rates (5.4/cancer) and minimal CIN-affected genomes (average of 4.5%) compared to MSS cohorts (p<0.0001). BRAFmut/MSS cancers had more frequent deletion CNAs compared to BRAFwt/MSS cancers on 6p and 17q at loci not typically correlated with colorectal cancer, and greater amplification CNAs on 8q and 18q compared to BRAFwt/MSS cancers. These results indicate that comparable rates of CIN occur between MSS subgroups, however significant differences in their patterns of instability exist, with BRAFmut/MSS cancers showing a 'focal pattern' and BRAFwt/MSS cancers having a 'whole arm pattern' of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers provides further evidence of the biological distinctions of this important cancer subgroup.

Project description:Purpose:The aim of this study was to investigate the prognostic value of the combination of microsatellite instability (MSI) and BRAF V600E mutation in colorectal cancer (CRC). Materials and methods:We compare the prognosis difference among CRC patients with four subtypes according to MSI and BRAF mutation, ie, microsatellite stable/BRAF wild type (MSS/BRAFwt), MSS/BRAF mutation (MSS/BRAFmut), MSI/BRAFwt, and MSI/BRAFmut, by pooling the previous related reports and public available data sets till December 2017 for the first time. Results:Twenty-seven independent studies comprising 24,067 CRC patients were included. Meta-analysis suggested that, compared with MSS/BRAFwt subtype, MSS/BRAFmut was associated with shorter overall survival (OS) (N=25, HR = 2.018, 95% CI = 1.706-2.388, P=2.220E-16), while there was a trend of association of MSI/BRAFmut with OS (N=13, HR = 1.324, 95% CI = 0.938-1.868, P=1.096E-01) and no association of MSI/BRAFwt with OS (N=17, HR = 0.996, 95% CI = 0.801-1.240, P=9.761E-01). Compared with MSI/ BRAFwt subtype, MSI/BRAFmut was a poor factor for OS (N=22, HR = 1.470, 95% CI = 1.243-1.740, P=7.122E-06). Compared with MSS/BRAFmut subtype, both MSI/BRAFwt (N=11, HR = 0.560, 95% CI = 0.433-0.725, P=1.034E-05) and MSI/BRAFmut (N=16, HR = 0.741, 95% CI = 0.567-0.968, P=2.781E-02) were favorable for OS. Subgroup analysis revealed similar results in all subgroups except the subgroup of stage IV cancer, in which MSI showed poor effects on OS in BRAF wild-type patients (N=6, HR = 1.493, 95% CI = 1.187-1.879, P=6.262E-04) but not in BRAF-mutated patients (N=5, HR = 1.143, 95% CI = 0.789-1.655, P=4.839E-01). Meta-analysis regression and test of interaction revealed no interaction of MSI with BRAF mutation when evaluating the associations of MSI/BRAF mutation subtypes with OS in CRC. Conclusion:Among the four subtypes according to MSI and BRAF mutation, MSS/BRAFmut was a poor prognostic factor, while MSS/BRAFwt and MSI/BRAFwt were comparable and favorable and MSI/BRAFmut was moderate in CRC. The combination of MSI/BRAF mutations could facilitate the planning of individualized treatment strategies and prognosis improvement in CRC.

Project description:ObjectivesMicrosatellite instability (MSI) status is an important hallmark for prognosis prediction and treatment recommendation of colorectal cancer (CRC). To address issues due to the invasiveness of clinical preoperative evaluation of microsatellite status, we investigated the value of preoperative 18F-FDG PET/CT radiomics with machine learning for predicting the microsatellite status of colorectal cancer patients.MethodsA total of 173 patients that underwent 18F-FDG PET/CT scans before operations were retrospectively analyzed in this study. The microsatellite status for each patient was identified as microsatellite instability-high (MSI-H) or microsatellite stable (MSS), according to the test for mismatch repair gene proteins with immunohistochemical staining methods. There were 2,492 radiomic features in total extracted from 18F-FDG PET/CT imaging. Then, radiomic features were selected through multivariate random forest selection and univariate relevancy tests after handling the imbalanced dataset through the random under-sampling method. Based on the selected features, we constructed a BalancedBagging model based on Adaboost classifiers to identify the MSI status in patients with CRC. The model performance was evaluated by the area under the curve (AUC), sensitivity, specificity, and accuracy on the validation dataset.ResultsThe ensemble model was constructed based on two radiomic features and achieved an 82.8% AUC for predicting the MSI status of colorectal cancer patients. The sensitivity, specificity, and accuracy were 83.3, 76.3, and 76.8%, respectively. The significant correlation of the selected two radiomic features with multiple effective clinical features was identified (p < 0.05).Conclusion18F-FDG PET/CT radiomics analysis with the machine learning model provided a quantitative, efficient, and non-invasive mechanism for identifying the microsatellite status of colorectal cancer patients, which optimized the treatment decision support.

Dataset Information

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

Publications

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

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