Germline Mutations in SUFU Cause Gorlin Syndrome–Associated Childhood Medulloblastoma and Redefine the Risk Associated With PTCH1 Mutations

Abstract

We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…A natural occurring mutation (S352F) abolishing S352 phosphorylation has been described in the medulloblastoma of patients affected by Gorlin syndrome (Smith et al , 2014). Therefore, we tested Fbxl17 binding to Sufu S352F.…”

“…This substitution appears in the medulloblastoma of patients affected by Gorlin syndrome and contributes to the medulloblastoma development, in the absence of other alterations in Hh pathway (Smith et al , 2014). We observed that the half‐life of Sufu S352F was found to be decreased compared to Sufu WT, in accordance with an increased binding to Fbxl17.…”

“…Importantly, heterozygous loss of Sufu, in conjunction with the loss of p53, leads to the development of medulloblastoma and rhabdomyosarcoma (Lee et al , 2007). Germline Sufu mutations have been identified in medulloblastoma (Taylor et al , 2002; Kool et al , 2014) and associated with the development of medulloblastoma in Gorlin syndrome (Pastorino et al , 2009; Kijima et al , 2012; Smith et al , 2014). Furthermore, somatic Sufu mutations have been identified in multiple other malignancies, including prostate cancer (Sheng et al , 2004).…”

An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region

“…The syndrome is inherited in an autosomal dominant manner and has been associated with mutation in the SUFU (Suppressor of fused) gene, which acts downstream of PTCH1 in the Hedgehog biochemical pathway. Mutation of SUFU in the absence of PTCH1 mutations has been described in patients meeting the diagnostic criteria of classic nevoid basal cell carcinoma syndrome [38][39][40]. In the cases thus far described, patients did not develop odontogenic keratocysts and showed a greater risk of medulloblastoma and meningioma.…”

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

“…In addition, sporadic BCCs without PTCH1 mutations have been reported to harbor gain-of-function SMO mutations (12,32). A few cases of familial SUFU mutations have been identified, which have very recently been linked to BCC occurrence (33,34).…”