Cancer Res Treat.  2023 Oct;55(4):1270-1280. 10.4143/crt.2023.415.

Specific Mutations in APC, with Prognostic Implications in Metastatic Colorectal Cancer

• Peng H
• Ying J
• Zang J
• Lu H
• Zhao X
• Yang P
• Wang X
• Li J
• Gong Z
• Zhang D
• Wang Z

• KMID: 2547801
• DOI: http://doi.org/10.4143/crt.2023.415

Abstract

Purpose
Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.
Materials and Methods
Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed.
Results
APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations.
Conclusion
APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.

Keyword

Metastatic colorectal cancer; Tumor mutation burden; Prognosis; RTK/RAS; Wnt; TGFβ

Figure

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  Fig. 1 Mutation overview of collected samples. The variant classification (A), variant type (B), and single nucleotide variation (SNV) class (C) of mutated genes involved in metastatic colorectal cancer (mCRC) tumors; variants in each sample (D); summary of variant classification (E); mutation types of the top 10 genes (F); the water-fall diagram indicated the Top 20 mutated genes and their variant types in mCRC tissues based on next generation sequencing data from collected samples (G). 60− or 60+ represents the patients younger or older than 60 years at diagnosis with mCRC. APC, adenomatous polyposis coli.

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  Fig. 2 Tumor mutation burden (TMB) correlation with adenomatous polyposis coli (APC) specific mutation and sex. (A) No significant relationship showed between TMB and APC mutated or not. (B) APC C-terminal side alteration showed a higher TMB score than N-terminal side alteration. (C) Female metastatic colorectal cancer patients showed higher TMB than male. (D) No significant relationship showed between TMB and age at diagnosis. “ns” and “***” indicate p > 0.05, and p < 0.001, Wilcox test.

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  Fig. 3 Results validation of clinical indicators about tumor mutation burden (TMB) using public databases: (A) APC group, (B) sex, and (C) age at diagnosis. “ns”, “*” and “****” indicate p > 0.05, p < 0.05 and p < 0.0001, respectively, Wilcox test.

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  Fig. 4 The prognostic value of adenomatous polyposis coli (APC) specific mutation in metastatic colorectal cancer patients.

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  Fig. 5 Genetic analysis of the difference in adenomatous polyposis coli (APC) specific mutation. (A) Distribution of mutations in the APC gene and their position relative to the split point for the N-terminal and C-terminal groups. (B) Frequency of oncogenic pathway alterations by APC mutation side. (C) Count of oncogenic pathway-related gene alterations by APC mutation side. (D) Frequency of concurrent oncogenic alterations by APC mutation side. “*”, “**” and “***” indicates p < 0.05, p < 0.01, and p < 0.001, respectively, Wilcox test.

Reference

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