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Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma
You-Kang Chang1,2, Hui-Hwa Tseng3, Chung-Man Leung4
1Department of Radiation Oncology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan.
Abstract:
This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.
Insights
Gene mutations in rectal cancer impact treatment outcomes. Specific mutations like BRAF, SMAD4, and TP53 were linked to patient response after neoadjuvant chemoradiotherapy (nCRT).
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Rectal carcinoma treatment outcomes vary significantly.
- Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment, but response prediction remains challenging.
- Understanding the genetic landscape of rectal tumors is crucial for personalized treatment strategies.
Purpose of the Study:
- To investigate the role of oncogenic and tumor-suppressive gene mutations in differential patient outcomes following nCRT for rectal carcinoma.
- To identify specific gene mutations associated with complete or poor response to nCRT.
Main Methods:
- Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) rectal carcinoma specimens.
- Gene mutation status was analyzed before and after nCRT using the AmpliSeq platform.
- Mutation profiles were compared between patients with complete and poor responses to nCRT.
Main Results:
- High frequencies of mutations were observed in TP53 (93.1%), APC (65.5%), KRAS (48.6%), CDKN2A (31%), and EGFR (31%).
- Mutations in ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53 were more frequent in patients with a complete response.
- APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations persisted after nCRT.
Conclusions:
- Rectal carcinoma exhibits a complex mutational profile.
- BRAF, SMAD4, and TP53 genetic variants are implicated in treatment outcomes for patients receiving nCRT.
- These findings may inform the development of targeted therapies and predictive biomarkers for rectal cancer.
