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

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• Attenuated familial adenomatous polyposis (AFAP) is an inherited condition associated with colorectal cancer risk due to APC gene variants.
• Salivary gland tumors are rare and have not been previously linked to AFAP.

Purpose of the Study:

• To investigate the association between AFAP and salivary gland tumors.
• To explore the molecular mechanisms underlying salivary gland tumor development in AFAP patients.

Main Methods:

• Case study of a family with AFAP and multiple salivary gland tumors.
• Analysis of tumor samples for β-catenin staining, APC locus alterations (CNN-LOH), and CTNNB1 mutations.
• Spatial transcriptomic analysis of salivary lesions to assess WNT pathway gene expression.

Main Results:

• The study identified basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) in a family with AFAP.
• Abnormal nuclear β-catenin staining was observed in both colon and salivary gland tumors.
• Genomic analysis revealed APC locus alterations in parotid BCACs and a CTNNB1 mutation in a submandibular BCAC.
• WNT pathway gene expression increased progressively from benign to malignant salivary lesions.

Conclusions:

• Basal cell adenomas and adenocarcinomas are potential new phenotypes of AFAP.
• Loss of APC function and WNT pathway activation are implicated in the development of these salivary gland tumors in AFAP.
• This expands the clinical spectrum of AFAP and highlights the role of the WNT pathway in its pathogenesis.