<i>ERBB3</i>-Activating Mutations in Small Bowel Adenocarcinomas.

Abstract

Functional studies have demonstrated that some mutations of <i>ERBB3</i>, 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 <i>ERBB3</i>-mutated cancers. This study was designed to report the rate of activating <i>ERBB3</i> mutations in small bowel adenocarcinoma (SBA), a rare tumor type in which we previously reported a high rate (12%) of <i>ERBB2</i>-activating mutations. DNA from 74 SBAs, previously characterized for <i>ERBB2</i> mutations and mismatch repair status, was submitted for sequencing of <i>ERBB3</i> exons 3, 6, 7, 8, and 23. Orthogonal validation by targeted next-generation sequencing was performed. Four of 74 SBAs (5.4%) displayed <i>ERBB3</i>-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. <i>ERBB3</i>-activating mutations were associated with microsatellite instability (<i>P</i> = .002) and the presence of <i>ERBB2</i>-activating mutations (<i>P</i> = .002). Two SBAs with co-occurrence of <i>ERBB2</i> and <i>ERBB3</i> 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. SBAs display a high rate of <i>ERBB3</i>-activating mutations, which have been shown to be targetable by anti-HER2 therapies. Strikingly, <i>ERBB3</i> was frequently comutated with <i>ERBB2</i>, suggesting a strong oncogenic addiction of these SBAs to the HER2 pathway.