Functional studies have demonstrated that mutations of the ERBB3 oncogene, which encodes the HER3 receptor, are oncogenic through the activation of the HER2 signalling pathway (Jaiswal et al, Cancer Cell 2013). We and other have reported a significant clinical activity of anti-HER2 therapy in patients with ERBB3-mutated cancers (trastuzumab/lapatinib combination: Bidard et al, Ann Oncol 2015; afatinib: Choudury et al, JCO 2016). This study aimed at reporting the rate of activating ERBB3 mutations in small bowel adenocarcinoma (SBC), a rare tumor type in which we previously reported a high rate (12%) of activating ERBB2 mutations (Laforest et al, Eur J Cancer 2014).
DNA from 74 SBC, which have been previously characterized for ERBB2 mutations and MSI status, were subjected to HRM analysis followed by Sanger sequencing of ERBB3 exons 3, 6, 7, 8 and 23. Orthogonal validation by targeted NGS was performed for two patients (HiSeq, 50 genes, mean depth 10000x)
4 of the 74 SBC (5.4%) displayed activating ERBB3 mutations, including 3 p.V104M mutations (c.310 G>A) in exon 3 and 1 p.E928G mutation (c.2783 A>G) in exon 23. No mutation was detected in exon 6, 7 and 8. Activating ERBB3 mutations were associated with microsatellite instability (p = 0.002) and with the presence of activating ERBB2 mutations (p = 0.002). 2 SBC cases with a co-occurrence of ERBB2 and ERBB3 mutations were further analyzed by targeted NGS: in addition to confirming the co-occurence of these activating mutations, mutant allelic frequencies did not suggest a subclonal distribution: 24.3% (ERBB3 p.V104M) vs 25.9% (ERBB2 p.L755S) and 18.5% (ERBB3 p.V104M) vs 24.5% (ERBB2 p.L755S) vs 20.6% (BRCA2 p.Q1782fs) in the first and second case, respectively.
SBC display a high rate of ERBB3 activating mutations, which have been shown to be targetable by anti-HER2 therapies. Strikingly, in most cases, ERBB3 was co-mutated with ERBB2, suggesting a strong oncogenic addiction of these SBC to the HER2 pathway.
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All authors have declared no conflicts of interest.