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Published on: July 25, 2020
Driver and targetable alterations in Chinese patients with small bowel carcinoma
Jun Li1, Xiaomo Li2, Ningning Dong3
1Department of General Surgery, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Purpose:
Small bowel carcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis. Recent genomic profiling studies revealed that the landscape of molecular alterations in SBA was distinct from colorectal cancer (CRC) and gastric cancer (GC). To explore driver and targetable alterations in SBA, we performed next-generation sequencing in 107 Chinese SBA patients.
Methods:
DNA from paraffin-embedded SBA samples and the corresponding peripheral blood control samples were analyzed through a next-generation sequencing panel. Somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants were characterized.
Results:
More than half of SBA cases carried KRAS mutations, including canonical (G12, G12, Q61) and atypical mutations (A146, L19, and K117). To our best knowledge, this was the first report of rare driver alterations including KRAS A146V/L19F, PIK3CA N345K/G364R/Q546E, and ZKSCAN1-MET fusion in SBA. Compared to KRAS-mutant patients, alternative activating alterations were enriched in KRAS wild-type patients, and some of them are targetable. Among BRAF-mutated SBA patients, class 1/2 BRAF mutants were mutually exclusive with RAS mutations, but class 3 BRAF mutants were not. Activating ERBB2 alternations, including amplification and activating mutations, represent the most common targetable alternation in this SBA cohort. Of note, the spectrums of BRAF and PIK3CA mutations in this Chinese SBA cohort were distinct from those of a European SBA cohort. Patients with three druggable mutations (PIK3CA, MAP2K1, KRAS G12C) had a high prevalence of concurring drivers, which may interfere with the clinical efficacy of single-target therapy.
Conclusion:
Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.
Insights
Genomic profiling of 107 Chinese small bowel carcinoma (SBA) patients revealed distinct molecular alterations. Identifying targetable mutations like KRAS, BRAF, and ERBB2 is crucial for advancing precision oncology in SBA.
Area of Science:
- Oncology
- Genomics
- Gastroenterology
Background:
- Small bowel carcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis.
- Molecular alterations in SBA differ from colorectal cancer (CRC) and gastric cancer (GC).
Purpose of the Study:
- To identify driver and targetable molecular alterations in Chinese SBA patients.
- To understand the genomic landscape of SBA through next-generation sequencing.
Main Methods:
- Next-generation sequencing (NGS) of DNA from 107 Chinese SBA patient samples and peripheral blood controls.
- Characterization of somatic alterations including point mutations, indels, copy number alterations, and gene fusions.
- Identification of pathogenic germline variants.
Main Results:
- Over half of SBA cases harbored KRAS mutations.
- Novel driver alterations (e.g., KRAS A146V/L19F, PIK3CA N345K/G364R/Q546E, ZKSCAN1-MET fusion) were identified.
- Activating ERBB2 alterations were the most common targetable alterations; BRAF and PIK3CA mutation spectra differed from European cohorts.
- Concurrent druggable mutations were prevalent, potentially impacting single-target therapy efficacy.
Conclusions:
- This study provides a comprehensive analysis of driver and targetable alterations in SBA.
- Findings can guide precision oncology strategies for SBA treatment.
- Understanding the distinct molecular profile of Chinese SBA patients is essential.
