Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Naturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 90 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 37% of canine pulmonary adenocarcinomas (cPAC, 28/76), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, KRAS, and TP53 were the most frequently mutated genes (18% each). In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (12%), SMAD4 (5.3%), PTEN (5.3%), and VHL (4.0%). cPACs assessed by exome sequencing displayed a low mutation burden (median 64 SNVs, 19 CNVs and 1 SV). The majority (93%) of HER2 mutations are hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular and TMD. The HER2 V659E mutation was detected in the plasma of 33% (2/6) of dogs with localized tumors bearing this mutation. HER2 V659E correlated with constitutive phosphorylation of Akt in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2 wild-type cell lines. These findings have immediate translational and comparative relevance for lung cancer and HER2 inhibition.