Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients

Sum-Fu Chiang; Heng-Hsuan Huang; Wen-Sy Tsai; Bertrand Chin-Ming Tan; Chia-Yu Yang; Po-Jung Huang; Ian Yi-Feng Chang; Jiarong Lin; Pei-Shan Lu; En Chin; Yu-Hao Liu; Jau-Song Yu; Jy-Ming Chiang; Hsin-Yuan Hung; Jeng-Fu You; Hsuan Liu

Biomedical Journal (Apr 2022)

Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients

Sum-Fu Chiang,
Heng-Hsuan Huang,
Wen-Sy Tsai,
Bertrand Chin-Ming Tan,
Chia-Yu Yang,
Po-Jung Huang,
Ian Yi-Feng Chang,
Jiarong Lin,
Pei-Shan Lu,
En Chin,
Yu-Hao Liu,
Jau-Song Yu,
Jy-Ming Chiang,
Hsin-Yuan Hung,
Jeng-Fu You,
Hsuan Liu

Affiliations

Sum-Fu Chiang: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Heng-Hsuan Huang: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Wen-Sy Tsai: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Bertrand Chin-Ming Tan: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Chia-Yu Yang: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
Po-Jung Huang: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Ian Yi-Feng Chang: Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
Jiarong Lin: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
Pei-Shan Lu: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
En Chin: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Yu-Hao Liu: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Jau-Song Yu: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
Jy-Ming Chiang: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Hsin-Yuan Hung: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Jeng-Fu You: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Hsuan Liu: Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Corresponding author. Graduate Institute of Biomedical Sciences and Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, 259 Wenhua 1st Rd., Gueishan, Taoyuan 333, Taiwan.

Journal volume & issue: Vol. 45, no. 2
pp. 347 – 360

Abstract

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Background: Colorectal cancer (CRC) is a major health concern globally, but exhibits regional and/or environmental distinctions in terms of outcome especially for patients with stage III CRC. Methods: From 2014 to 2016, matched pairs of tumor and adjacent normal tissue samples from 60 patients with stage I–IV CRC from Chang Gung Memorial Hospital in Taiwan were analyzed using next-generation sequencing. The DNA, mRNA, and miRNA sequences of paired tumor tissues were profiled. An observational study with survival analysis was done. Online datasets of The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) were also integrated and compared. Results: The gene that exhibited the highest mutation rate was adenomatous polyposis coli (APC) (75.0%), followed by TP53 (70.0%), KRAS (56.6%), and TTN (48.3%). APC was also the most frequently mutated gene in TCGA and ICGC datasets. Surprisingly, for non-metastatic cases (stages I-III), CRC patients with mutated APC had better outcome in terms of overall survival (p = 0.041) and recurrence free survival (p = 0.0048). Particularly for stage III CRC, the overall survival rate was 94.4% and 67.7%, respectively (p = 0.018), and the recurrence free survival rate was 94.4% and 16.7%, respectively (p = 0.00044). Further clinical and gene expression analyses revealed that the APC wt specimens to a greater extent exhibit poor differentiation state as well as EGFR upregulation, providing molecular basis for the poor prognosis of these patients. Finally, based on integrated transcriptome analysis, we constructed the mRNA-miRNA networks underlying disease recurrence of the stage III CRC and uncovered potential therapeutic targets for this clinical condition. Conclusion: For stage III CRC, patients with mutated APC had better overall and recurrence free survival.

Published in Biomedical Journal

ISSN: 2319-4170 (Print); 2320-2890 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: https://www.sciencedirect.com/journal/biomedical-journal

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