Genomic Landscape Analysis of Canine Pulmonary Adenocarcinoma Reveals Candidate Targetable Gene Fusions.

Abstract

Spontaneously occurring primary canine pulmonary adenocarcinoma (cPAC) exhibits clinicopathological and molecular similarities to never-smoker human lung cancers. Shared genomic alterations, including point mutations, indel mutations and copy number changes particularly in HER2 signalling, are significant therapeutic targets, especially for HER2 and tyrosine kinase inhibitors. Whilst progress has been made in identifying mutational drivers in canine cancers, the role of somatic gene fusions in cPAC remains poorly understood, despite their importance in other cancers as drivers and therapeutic targets. This study investigates the fusion landscape in cPAC by analysing RNA-seq data from a cohort of 36 primary tumour samples and reports oncogenic fusions with therapeutic potential. Notably, NRG1 fusions were identified in a subset of tumours, including recurrent SDC4::NRG1 events, potentially playing key roles in disease progression. NRG1 fusions, known to activate HER2 signalling, are mutually exclusive with HER2 gene alterations, indicating convergence on the same pathway. Tumours with SDC4::NRG1 fusions also overexpress HER2 pathway-related genes, reinforcing NRG1-driven activation. Similar fusions occur in never-smoker human non-small cell adenocarcinoma lacking other common drivers, underscoring their therapeutic importance. These findings highlight NRG1 fusions as critical contributors to cPAC tumorigenesis and warrant further clinical and comparative investigation. Additionally, novel fusions disrupting the PTEN axis were identified, leading to truncated PTEN and associated protein domains. These disruptions could impair tumour-suppressive pathways, presenting additional therapeutic targets. This research emphasises the broader relevance of fusion-driven mechanisms in cPAC tumorigenesis, advancing the understanding of both canine and human lung cancers for clinical and comparative studies.