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

Frontiers in Oncology
Peng-Chan LinMeng-Ru Shen

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 studi...Continue Reading

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Citations

Mar 7, 2021·Cancers·Nayden G NaydenovAndrei I Ivanov

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Methods Mentioned

BETA
surgical resection
fluorescence
genotyping
light microscopy
targeted-gene
targeted-gene sequencing
transfection

Software Mentioned

R package randomForest
ImageJ
FastQC
R
SciClone
LASSO
survminer
DeepSNV
R package
CloneEvol

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