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Updated: Oct 4, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
ERBB3-Activating Mutations in Small Bowel Adenocarcinomas
Luc Cabel1, Thomas Aparicio1, Ivan Bieche1
1Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France.
Purpose:
Functional studies have demonstrated that some mutations of ERBB3, which encodes for human epidermal growth factor receptor (HER) 3, are oncogenic via activation of the ErbB family signaling pathway. Significant clinical activity of anti-HER2 therapies (trastuzumab plus lapatinib combination or afatinib) has been reported in patients with ERBB3-mutated cancers. This study was designed to report the rate of activating ERBB3 mutations in small bowel adenocarcinoma (SBA), a rare tumor type in which we previously reported a high rate (12%) of ERBB2-activating mutations.
Materials And Methods:
DNA from 74 SBAs, previously characterized for ERBB2 mutations and mismatch repair status, was submitted for sequencing of ERBB3 exons 3, 6, 7, 8, and 23. Orthogonal validation by targeted next-generation sequencing was performed.
Results:
Four of 74 SBAs (5.4%) displayed ERBB3-activating mutations, including three p.V104M mutations (c.310 G>A) in exon 3 and one p.E928G mutation (c.2783 A>G) in exon 23. No mutations were detected in exons 6, 7, and 8. ERBB3-activating mutations were associated with microsatellite instability (P = .002) and the presence of ERBB2-activating mutations (P = .002). Two SBAs with co-occurrence of ERBB2 and ERBB3 mutations were further analyzed by targeted next-generation sequencing. Mutant allelic frequencies suggested that both mutations were shared by the same clone rather than being harbored by mutually exclusive tumor subclones.
Conclusion:
SBAs display a high rate of ERBB3-activating mutations, which have been shown to be targetable by anti-HER2 therapies. Strikingly, ERBB3 was frequently comutated with ERBB2, suggesting a strong oncogenic addiction of these SBAs to the HER2 pathway.
Insights
Activating mutations in ERBB3 (human epidermal growth factor receptor 3) occur in 5.4% of small bowel adenocarcinomas. These ERBB3 mutations are targetable with anti-HER2 therapies and often co-occur with ERBB2 mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in ERBB3 (human epidermal growth factor receptor 3) can drive cancer through the ErbB signaling pathway.
- Anti-HER2 therapies show clinical activity in cancers with ERBB3 mutations.
- Small bowel adenocarcinoma (SBA) is a rare cancer with a previously reported 12% rate of ERBB2 mutations.
Purpose of the Study:
- To determine the frequency of activating ERBB3 mutations in small bowel adenocarcinoma (SBA).
- To investigate the association between ERBB3 mutations and ERBB2 mutations in SBA.
- To explore the potential for targeted therapies in ERBB3-mutated SBAs.
Main Methods:
- Sequencing of key ERBB3 exons (3, 6, 7, 8, 23) in DNA from 74 SBAs.
- Orthogonal validation using targeted next-generation sequencing.
- Analysis of associations between ERBB3 mutations, ERBB2 mutations, and microsatellite instability.
Main Results:
- Activating ERBB3 mutations were identified in 5.4% (4/74) of SBAs.
- The identified mutations were p.V104M in exon 3 and p.E928G in exon 23.
- ERBB3 mutations were significantly associated with microsatellite instability (P = .002) and the presence of ERBB2 mutations (P = .002).
- Co-occurring ERBB2 and ERBB3 mutations suggested they originated from the same tumor clone.
Conclusions:
- Small bowel adenocarcinomas exhibit a notable frequency of activating ERBB3 mutations.
- These ERBB3 mutations are potentially targetable with existing anti-HER2 therapies.
- Frequent co-mutation of ERBB2 and ERBB3 suggests a strong dependence on the HER2 pathway in a subset of SBAs.
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