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.

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

“…The roles of another member of class XVIII myosins, MYO18A, in oncogenesis remain poorly characterized. A recent study identified frequent MYO18A mutations in stage III CRC [ 59 ]. These mutations appear to be an independent prognostic factor of clinical outcomes and were significantly associated with increased disease-free patient survival [ 59 ].…”

“…A recent study identified frequent MYO18A mutations in stage III CRC [ 59 ]. These mutations appear to be an independent prognostic factor of clinical outcomes and were significantly associated with increased disease-free patient survival [ 59 ]. Since the CRC-associated mutations of MYO18A have not been linked to altered expression or activity of this protein, it is difficult to establish whether their beneficial effect is due to the loss- or gain-of-function of MYO18A.…”

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

“…The survival rate of metastatic CRC patients beyond five years from diagnosis remains less than 20% [1], and approximately 40% of non-metastatic tumors will recur after completing surgical resection [1]. With the notable exception of BRAF V600E mutant tumors [5], other solid tumors targeted therapies (such as tyrosine kinase inhibitors, and immune therapies) have shown little benefit in CRC [6][7][8]. Existing evidence suggests that intra-tumor genetic, epigenetic, and transcriptomic heterogeneity among tumor subclones causes poor prognosis, metastasis, tumor recurrence, and drug resistivity of the CRC patients [7,[9][10][11][12][13][14].…”

“…With the notable exception of BRAF V600E mutant tumors [5], other solid tumors targeted therapies (such as tyrosine kinase inhibitors, and immune therapies) have shown little benefit in CRC [6][7][8]. Existing evidence suggests that intra-tumor genetic, epigenetic, and transcriptomic heterogeneity among tumor subclones causes poor prognosis, metastasis, tumor recurrence, and drug resistivity of the CRC patients [7,[9][10][11][12][13][14].…”

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy

“…With advances in NGS technology, tumor-targeted sequencing is becoming an affordable tool for patients with cancer. Indeed, these advances enhanced our ability to identify the impact of tumor heterogeneity and evolution when developing drug response genetic markers in our previous study [ 16 ]. To address these issues, we performed a cancer genomics evolutionary trajectory analysis.…”