Medulloblastoma and other neoplasms in patients with heterozygous germline SUFU variants: A scoping review

In 2002, heterozygous suppressor of fused variants (SUFU^+/-) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU^+/- variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome or Gorlin-Goltz syndrome; OMIM 109400), an autosomal-dominant cancer predisposition syndrome. The phenotype of patients with germline SUFU^+/- variants is very poorly characterized due to a paucity of large studies with long-term follow-up. As such, there is a clinical need to better characterize the spectrum of neoplasms among patients with germline SUFU^+/- variants so that clinicians can provide accurate counseling and optimize tumor surveillance strategies. The objective of this study is to perform a scoping review to map the evidence on the rate of medulloblastoma and to describe the spectrum of other neoplasms among patients with germline SUFU^+/- variants. A review of all published literature in PubMed (MEDLINE), EMBASE, Cochrane, and Web of Science were searched from the beginning of each respective database until October 9, 2021. Studies of pediatric and adult patients with a confirmed germline SUFU^+/- variant who were evaluated for the presence of any neoplasm (benign or malignant) were included. There were 176 patients (N = 30 studies) identified with a confirmed germline SUFU^+/- variant who met inclusion criteria. Data were extracted from two cohort studies, two case-control studies, 18 case series, and eight case reports. The median age at diagnosis of a germline SUFU^+/- variant was 4.5 years where 44.4% identified as female and 13.4% of variants were de novo. There were 34 different neoplasms (benign and malignant) documented among patients with confirmed germline SUFU^+/- variants, and the most common were medulloblastoma (N = 59 patients), BCC (N = 21 patients), and meningioma (N = 19 patients). The median age at medulloblastoma diagnosis was 1.42 years (range 0.083-3; interquartile range 1.2). When data were available for these three most frequent neoplasms (N = 95 patients), 31 patients (32.6%) had neither MB, BCC nor meningioma; 51 patients (53.7%) had one of medulloblastoma or BCC or meningioma; eight patients (8.4%) had two of medulloblastoma or BCC or meningioma, and five patients (5.3%) had medulloblastoma and BCC and meningioma. This is the first study to synthesize the data on the frequency and spectrum of neoplasms specifically among patients with a confirmed germline SUFU^+/- variant. This scoping review is a necessary step forward in optimizing evidence-based tumor surveillance strategies for medulloblastoma and estimating the risk of other neoplasms that could impact patient outcomes.