Abstract
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.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Abbreviations
- ACMG:
-
American College of Medical Genetics and Genomics
- AMP:
-
Association for molecular pathology
- ADC:
-
Antibody–drug conjugates
- CRC:
-
Colorectal cancer
- dMMR:
-
MMR deficiency
- DDR:
-
DNA damage repair
- ECD:
-
Extracellular domain
- FFPE:
-
Formalin‐fixed paraffin‐embedded
- FAP:
-
Familial adenomatous polyposis
- GC:
-
Gastric cancer
- HRD:
-
Homologous recombination deficiency
- JMD:
-
Juxtamembrane domain
- KD:
-
Kinase domain
- LS:
-
Lynch syndrome
- MAPK TT:
-
MAPK-targeted therapy
- MSI:
-
Microsatellite instability
- MSS:
-
Microsatellite stable
- MSI-H:
-
High microsatellite instability
- NCCN:
-
National Comprehensive Cancer Network
- NGS:
-
Next-generation sequencing
- PGV:
-
Pathogenic germline variant
- P/LP:
-
Pathogenic/likely pathogenic
- PJS:
-
Peutz–Jeghers syndrome
- SBA:
-
Small bowel adenocarcinoma
- SV:
-
Structural variation
- TKI:
-
Tyrosine kinase inhibitor
- TD:
-
Transmembrane domain
- VAF:
-
Variant allele frequency
- WT:
-
Wild-type MAPK TT: MAPK-targeted therapy
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Acknowledgements
The authors are grateful to the patients for their kind cooperation.
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Concept and design: WD, YC, and CZ. Acquisition, analysis, and interpretation of data: JL, XL, ND, SY, and CJ. Drafting of the manuscript: XL and YC. Critical revision of the manuscript for important intellectual content: WD, TM, and CZ. Technical and material support: WL. Study supervision: WD, YC, and CZ. The work reported in the paper has been performed by the authors, unless clearly specified in the text.
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Xiaomo Li, Tonghui Ma, and Wei Li are employees of Hangzhou Jichenjunchuang Medical Laboratory, Co. Ltd, Hangzhou, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The retrospective study was approved by the Ethical Committee of the Beijing Friendship Hospital.
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432_2022_4521_MOESM1_ESM.pdf
Supplementary file1 Figure S1. Summary of somatic genomic alterations and their corresponding signaling pathways in 107 Chinese SBA patients. The majority signaling pathways altered in SBA include p53 pathway, RAF/RAS/MAPK, receptor tyrosine kinases, epigenetic modifiers, DNA damage repair, cell cycle, TGFβ, PI3K, Wnt and Notch (PDF 625 KB)
432_2022_4521_MOESM2_ESM.pdf
Supplementary file2 Figure S2. Pie chart showing the proportions of different KRAS variants in this Chinese SBA cohort (PDF 115 KB)
432_2022_4521_MOESM3_ESM.pdf
Supplementary file3 Figure S3. Four-generation family history pedigree. The proband in the current study cohort is indicated with an arrow (PDF 385 KB)
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Li, J., Li, X., Dong, N. et al. Driver and targetable alterations in Chinese patients with small bowel carcinoma. J Cancer Res Clin Oncol 149, 6139–6150 (2023). https://doi.org/10.1007/s00432-022-04521-0
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DOI: https://doi.org/10.1007/s00432-022-04521-0