Inherited Basaloid Neoplasms Associated With SUFU Pathogenic Variants

Area of Science:

• Dermatology
• Genetics
• Oncology

Background:

• Germline SUFU pathogenic variants (PVs) are known to cause basal cell nevus syndrome (BCNS) and multiple infundibulocystic basal cell carcinoma syndrome.
• The full spectrum of cutaneous findings associated with SUFU PVs requires further delineation.

Purpose of the Study:

• To define the clinical and histopathologic spectrum of cutaneous findings in patients with germline SUFU PVs.

Main Methods:

• Case series conducted in US academic dermatology, medical genetics, and medical oncology clinics (July 2014-July 2022).
• Included patients with confirmed germline SUFU PVs evaluated by a dermatologist.
• Histopathologic evaluation of skin biopsies and targeted next-generation sequencing (NGS) on tumor specimens.

Main Results:

• Five female patients presented with skin manifestations between ages 31-68 (mean 50.2 years), primarily in their fourth to sixth decades.
• Pathology revealed basaloid follicular hamartomas (BFHs), infundibulocystic basal cell carcinomas (iBCCs), nodular basal cell carcinomas (nBCCs), and infiltrative BCC.
• NGS suggested increased UV-signature variants in BCCs compared to BFHs.

Conclusions:

• Germline SUFU PVs can manifest as multiple indolent basaloid neoplasms alongside conventional BCCs, distinct from PTCH1 BCNS.
• Dermatologists and dermatopathologists should recognize this spectrum, as many lesions are indolent and may not require aggressive treatment.
• Therapies targeting smoothened (SMO) are unlikely to be effective due to SUFU's downstream position in the pathway.