Germline SUFU Mutations Cause Gorlin Syndrome and Increase Risk for Childhood Medulloblastoma


Key Points

  • Germline mutations in SUFU were identified as a cause of Gorlin syndrome in PTCH1-negative patients.
  • SUFU mutation is associated with increased risk of Gorlin syndrome–associated childhood medulloblastoma.

In a study to identify causative mutations in patients with Gorlin syndrome without PTCH1 mutations, Smith et al found that germline mutations in SUFU were associated with Gorlin syndrome and with increased likelihood of Gorlin syndrome–associated childhood medulloblastoma. The study is reported in the Journal of Clinical Oncology. As noted by the investigators, heterozygous germline PTCH1 mutations are known to cause Gorlin syndrome, but reported mutation detection rates rarely exceed 70%.

SUFU Mutation and Medulloblastoma

Exome sequencing was performed on lymphocyte DNA from four unrelated individuals in families with Gorlin syndrome who had no PTCH1 mutations identified on Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis. A germline heterozygous nonsense mutation in SUFU was found in one of the four exomes. Sanger sequencing of SUFU in 23 additional Gorlin syndrome families without PTCH1 mutations identified  SUFU mutation in a second family, and copy number analysis by MLPA identified a large heterozygous deletion in a third family.

The three SUFU-positive families met diagnostic criteria for Gorlin syndrome, although none of the affected individuals had odontogenic jaw keratocysts. All three families included a single case of medulloblastoma. In contrast, medulloblastoma occurred in only 2 (1.7%) of 115 patients with Gorlin syndrome and a PTCH1 mutation.

The investigators concluded: “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.”

D. Gareth R. Evans, MD, of Manchester Centre for Genomic Medicine, St Mary’s Hospital, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the British Skin Foundation and Manchester Biomedical Research Centre.

The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.