APC-related multiple salivary gland lesions: spatial transcriptomic analysis reveals progressive WNT activation

Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not been reported in AFAP before. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear beta-catenin staining. Genomic analysis of both parotid BCACs showed CNN-LOH at the APC locus, implicating loss of full-length APC in the aetiology of the parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband’s salivary lesions, from benign (intercalated duct hyperplasia and BCA) to malignant (BCACs). Our results showcase BCA and BCAC as new phenotypes of AFAP.