Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel
Alexander Quaas1, Carina Heydt2, Dirk Waldschmidt3
1Institute of Pathology, University of Cologne, Cologne, Germany. alexander.quaas@uk-koeln.de.
Background:
Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.
Methods:
We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).
Results:
In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.
Conclusion:
Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.
Insights
Potentially treatable molecular alterations, including BRCA mutations and ERBB2 or PIK3CA mutations, were identified in five small bowel carcinomas. Microsatellite instability was also found, highlighting targets for individualized cancer therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Small bowel carcinomas are rare and typically have a poor prognosis.
- Recent research has identified potentially targetable molecular alterations in these tumors.
- Individualized treatment strategies are increasingly relevant for small bowel carcinoma.
Purpose of the Study:
- To investigate the prevalence of treatable molecular alterations in small bowel carcinomas.
- To analyze DNA-based gene mutations and RNA-based gene fusions.
- To assess mismatch-repair deficiency in small bowel tumor samples.
Main Methods:
- Ultra-deep sequencing of 14 key genes (e.g., KRAS, BRAF, BRCA1/2, ERBB2, PIK3CA) using DNA panels.
- RNA-based gene fusion panel analysis for specific fusion genes.
- Microsatellite instability (MSI) testing and mismatch repair protein analysis.
Main Results:
- Potentially treatable genetic alterations were found in 5 of 11 small bowel carcinomas.
- BRCA1/2 mutations were identified in three patients, one with a mixed neuroendocrine-non-neuroendocrine neoplasm.
- Activating ERBB2 or PIK3CA mutations were found in two patients; two tumors were MSI-high, one associated with Lynch syndrome.
- No gene fusions were detected.
Conclusions:
- Molecular alterations such as ERBB2, BRCA, and MSI are significant in small bowel carcinomas.
- These findings support the potential for targeted therapies in small bowel cancer.
- Further research is necessary to confirm the efficacy of these targeted treatments.
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