Targeted deep sequencing reveals APC mutations as predictors of overall survival in Chinese colorectal patients receiving adjuvant chemotherapy

Abstract

Objective: Targeted deep sequencing was used to characterize the mutational spectrum of APC in Chinese colorectal tumors in comparison to that in Caucasians from The Cancer Genome Atlas (TCGA) and to investigate whether APC mutations can predict overall survival in CRC patients receiving adjuvant chemotherapy.

Methods: A total of 315 Chinese CRC patients including 241 stage II/III patients receiving fluorouracil-based adjuvant chemotherapy were included in this study. Next generation sequencing was carried out to detect somatic mutations on all APC exons. The associations between APC mutations and overall survival were determined by the Cox proportional hazards model.

Results: APC was mutated in 221 of 315 colorectal tumors (70.2%). Chinese CRC had a much higher frequency of missense mutations (16.2% vs. 2.4%), but a lower frequency of nonsense (41.0% vs. 54.2%) and frameshift mutations (10.5% vs. 18.4%) than Caucasian CRC. Among stage II/III patients receiving fluorouracil-based adjuvant chemotherapy, APC mutations showed a significant association with worse survival (HR = 1.69; 95% CI, 1.10-2.62; p = .0179). Of the mutation types, frameshift mutations conferred the highest risk of death (HR = 2.88; 95% CI, 1.54-5.37; p =.0009). Among individual mutation sites, Arg232Ter, the most frequent mutation in Chinese CRC, exhibited the strongest negative impact on survival (HR = 2.65; 95% CI, 1.16-6.03; p =.0202).

Conclusion: APC overall mutation was an independent predictor for overall survival of stage II/III CRC patients receiving fluorouracil-based chemotherapy.

Keywords:

• Targeted deep sequencing
• APC mutations
• predictors
• overall survival
• colorectal patients
• adjuvant chemotherapy

Author contributions

Lin MB, Li HG, Chen X and Hu MJ designed and managed the project. Chen Y, Li AJ and Jiang HH prepared clinical samples. Chen X, Hu MJ, Chen Y performed the experiments. Li HG, Li AJ, Hua YT and Jiang HH performed biological annotation. Li HG performed statistical analysis. Chen X and Li HG wrote the paper.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval

This study was reviewed and approved by the Yangpu Hospital Institutional Review Board.

Data availability statement

The data that supports the findings of this study are available in the supplementary material of this article.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [No.81874201 and No.32000539], the Natural Science Foundation of Shanghai of China [No.20ZR1452300], Shanghai Municipal Health Commission Foundation [No.201840359].