SUFU – Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is an autosomal dominant disorder characterized by developmental anomalies, multiple basal cell carcinomas (BCCs), odontogenic keratocysts, and an elevated risk of childhood medulloblastoma (PMID:19533801). While PTCH1 mutations underlie 50–85% of cases, the suppressor of fused homolog (SUFU) gene has been implicated in PTCH1-negative families presenting classic Gorlin features, including medulloblastoma.

Heterozygous SUFU germline variants encompass canonical splice-site (c.1022+1G>A), nonsense (c.550C>T (p.Gln184Ter)), and large deletion alleles identified in PTCH1-negative pedigrees (PMID:19533801, PMID:22829011). Exome sequencing in four unrelated PTCH1-negative families revealed SUFU mutations in two additional families, and MLPA detected a heterozygous deletion in a third, totaling four probands across three families (PMID:25403219). The variant spectrum includes loss-of-function mutations that co-segregate with Gorlin syndrome manifestations.

Segregation analysis demonstrated co-segregation of SUFU variants with medulloblastoma, meningioma, and multiple BCCs in at least four affected relatives across three independent pedigrees (PMID:25403219, PMID:31485359).

Functional studies reveal that tumor-derived SUFU mutations abrogate its repression of GLI transcription factors, leading to aberrant Hedgehog pathway activation and increased cellular proliferation in vitro and in vivo, consistent with the Gorlin syndrome phenotype (PMID:15077159). Structural and binding assays confirm impaired SUFU–GLI interaction for pathogenic SUFU alleles.

PTCH2 has been evaluated in PTCH1/SUFU-negative cohorts without identification of pathogenic variants, underscoring SUFU specificity in Gorlin syndrome etiology (PMID:34170463).

Collectively, SUFU loss-of-function mutations definitively cause a subset of Gorlin syndrome cases distinguished by high medulloblastoma penetrance. Clinical SUFU testing is recommended for PTCH1-negative individuals to refine diagnosis, guide MRI surveillance for early brain tumor detection, and inform personalized management. Key take-home: Autosomal dominant SUFU testing enhances diagnostic accuracy and enables targeted surveillance for medulloblastoma and basal cell carcinomas.

References

• American journal of medical genetics. Part A • 2009 • Identification of a SUFU germline mutation in a family with Gorlin syndrome. PMID:19533801
• Journal of clinical oncology • 2014 • Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. PMID:25403219
• Familial cancer • 2018 • Mutations in SUFU and PTCH1 genes may cause different cutaneous cancer predisposition syndromes: similar, but not the same. PMID:29356994
• Case reports in genetics • 2019 • Novel SUFU Frameshift Variant Leading to Meningioma in Three Generations in a Family with Gorlin Syndrome. PMID:31485359
• Familial cancer • 2012 • Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. PMID:22829011

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