Medulloblastoma and other Neoplasms in Patients with Heterozygous Germline SUFU Variants: A Scoping Review

Background: 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. Other neoplasms associated with pathologic germline SUFU^+/- variants have also been described among patients with basal cell nevus syndrome (BCNS; OMIM 109,400), 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 physicians can provide accurate counselling and optimize tumor surveillance strategies to allow for early detection and treatment of neoplasms, a cornerstone of optimizing patient outcomes.
Objective: 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.
Data sources: 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.
Participants, exposure, outcomes: 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.
Results: 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 a confirmed germline SUFU^+/- variants and the most common were medulloblastoma (N=59 patients), basal cell carcinoma (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 basal cell carcinoma or meningioma; 8 patients (8.4%) had two of medulloblastoma or BCC or meningioma and 5 patients (5.3%) had medulloblastoma and basal cell carcinoma and meningioma.
Conclusion: 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.