Dataset Information

Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer.

ABSTRACT: Many studies failed to demonstrate benefit from the addition of targeted agents to current standard adjuvant FOLFOX chemotherapy in stage III colorectal cancer (CRC) patients. Intratumor heterogeneity may foster the resistant subclones and leads to cancer recurrence. Here, we built a cancer evolution model and applied machine learning analysis to identify potential therapeutic targets. Among 78 CRC cases, whole-genome (WGS) and deep targeted sequencing data generated from paired blood and primary tumor were used for phylogenetic tree reconstruction. Genetic alterations in the PI3K/AKT, and RTK oncogenic signaling pathways were commonly detected in founding clones. The dominant subclones frequently exhibited dysregulations in the TP53, FBXW7/NOTCH1 tumor suppression, and DNA repair pathways. Fourteen genetic mutations were simultaneously selected by random forest and LASSO methods. The logistic regression model had better accuracy (79%), precision (70%), and recall (65%) and area under the curve (AUC) (82%) for cancer recurrence prediction. Three genes, including MYO18A in the founding clone, FBXW7, and ATM in the dominant subclone, affected the prognosis were selected simultaneously by different feature sets. The in vitro studies, HCT-116 cells transfected with MYO18A siRNA demonstrated a significant reduction in cell migration activity by 20-40%. These results indicate that MYO18A plays a crucial role in the migration of human CRC cells. The cancer evolution model revealed the critical mutations in the founding and dominant subclones. They can be used to predict clinical outcomes and the development of novel therapeutic targets for stage III CRC.

SUBMITTER: Lin PC

PROVIDER: S-EPMC7658598 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer.

Lin Peng-Chan PC Yeh Yu-Min YM Lin Bo-Wen BW Lin Shao-Chieh SC Chan Ren-Hao RH Chen Po-Chuan PC Shen Meng-Ru MR

Frontiers in oncology 20201029

Many studies failed to demonstrate benefit from the addition of targeted agents to current standard adjuvant FOLFOX chemotherapy in stage III colorectal cancer (CRC) patients. Intratumor heterogeneity may foster the resistant subclones and leads to cancer recurrence. Here, we built a cancer evolution model and applied machine learning analysis to identify potential therapeutic targets. Among 78 CRC cases, whole-genome (WGS) and deep targeted sequencing data generated from paired blood and primar ...[more]

PMID: 33194745

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Project description:Distant metastasis is the major causes of death in colorectal cancer (CRC) patients. In order to identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real-time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (P < 0.001). In stage II and stage III CRC, patients with low expression showed worse disease-free survival (P = 0.038). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in stage II and stage III CRC (relative risk, 9.532; 95% confidence interval, 2.303-41.905; P = 0.002). This study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients. Total of 111 microarray datasets (77 for LCM samples, and 17 pairs for homogenized samples from tumor and adjacent tissues) were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software together with BioConductor package, as described previously. Then, the gene expression levels were log2-transformed, and 62 control probe sets were removed for further analysis. In order to identify a set of genes associated with development of metastatic recurrence, we performed Wilcoxon rank-sum test for gene expression differences of 54,613 probe sets between recurrence and non-recurrence groups. Similarly, Wilcoxon singed-rank test was conducted to select genes which showed significant expression difference between tumor and adjacent tissue. Then, we selected a set of genes that satisfied both of above two criteria.

Dataset Information

Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer.

Publications

Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer.

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