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ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma
Anais Laforest1, Thomas Aparicio2, Aziz Zaanan1
1Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
Aim Of The Study:
Small bowel adenocarcinoma (SBA) is a rare and aggressive tumour with poor outcomes. Because of its low incidence, the number prospective studies remains insufficient leading to poor knowledge and absence of standard of care. Aiming to better understand small bowel carcinogenesis we investigated the frequency of somatic mutations in a large data set of patients in more than 740 mutational hotspots among 46 genes.
Methods:
In total, 83 SBA cases were selected from two European databases. The sequencing was performed using the Ion 316 Chip. Additionally we looked into ERBB2 expression and microsatellite instability (MSI) status.
Results:
The tumours most frequently were duodenal (47%) and stage ⩾3 (63%). Eight genes were mutated with a frequency >5%: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF and FBXW7. ERBB2 alterations are present in 10 patients (12%) through mutations (7 cases) or amplifications (3 cases). ERBB2 mutations were significantly associated with duodenal tumour location (P=0.04). In this group, there was a positive association with dMMR status (P=0.006) and APC mutation (P=0.02) but negative association with p53 mutations (P=0.038).
Conclusions:
This study describes the first large screening of somatic mutations in SBA using next generation sequencing. The ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumour location. In most cases ERBB2 mutation was identical (p.L755S). In clinical practice, this may suggest that more than 10% of the patients with SBA could be treated using an anti-ERBB2-targeted agent.
Insights
This study identified frequent ERBB2 mutations in small bowel adenocarcinoma (SBA), suggesting potential for targeted anti-ERBB2 therapy in over 10% of patients. Further research is needed to confirm these findings for rare gastrointestinal cancers.
Area of Science:
- Oncology
- Genetics
- Gastroenterology
Background:
- Small bowel adenocarcinoma (SBA) is a rare, aggressive gastrointestinal cancer with limited treatment options due to insufficient research.
- Understanding the molecular landscape of SBA is crucial for developing targeted therapies and improving patient outcomes.
Purpose of the Study:
- To investigate the frequency and spectrum of somatic mutations in a large cohort of small bowel adenocarcinoma (SBA) patients.
- To identify potential therapeutic targets by analyzing mutations in over 740 hotspots across 46 genes.
- To explore the role of ERBB2 alterations and microsatellite instability (MSI) in SBA pathogenesis.
Main Methods:
- Next-generation sequencing was performed on 83 SBA tumor samples from European databases.
- Analysis included mutation hotspots in 46 key cancer-associated genes.
- ERBB2 expression and microsatellite instability (MSI) status were also assessed.
Main Results:
- KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF, and FBXW7 were the most frequently mutated genes (>5%).
- ERBB2 alterations (mutations or amplifications) were found in 12% of patients, significantly associated with duodenal location.
- ERBB2 mutations showed associations with dMMR and APC mutations, but inversely with p53 mutations.
Conclusions:
- This study represents the first large-scale next-generation sequencing screening for somatic mutations in SBA.
- ERBB2 mutations are a frequent alteration in SBA, with their distribution influenced by tumor location.
- The high frequency of ERBB2 alterations suggests that a significant proportion of SBA patients may benefit from anti-ERBB2 targeted therapies.
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