Cancer risk and tumour spectrum in 172 patients with a germline<i>SUFU</i>pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group

Guerrini-Rousseau, Léa; Masliah‐Planchon, Julien; Waszak, Sebastian M.; Alhopuro, Pia; Benusiglio, Patrick R.; Bourdeaut, Franck; Brecht, Ines B.; Baldo, Giada Del; Dhanda, Sandeep Kumar; Garrè, Maria Luisa; Gidding, Corrie; Hirsch, Steffen; Hoarau, Pauline; Jørgensen, Mette; Kratz, Christian P.; Lafay‐Cousin, Lucie; Mastronuzzi, Angela; Pastorino, Lorenza; Pfister, Stefan M.; Schroeder, Christopher; Smith, Miriam J.; Vahteristo, Pia; Vibert, Roseline; Vilain, Catheline; Waespe, Nicolas; Winship, Ingrid; Evans, D Gareth; Brugières, Laurence

doi:10.1136/jmedgenet-2021-108385

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…In Kool et al's (2014) study, there were no cases of germline SUFU +/− variants detected in 33 pediatric patients who were diagnosed with medulloblastoma between ages 4 and 18 years and no germline SUFU +/− variants were detected in 33 patients who presented with medulloblastoma as adults. In a more recent publication by Guerrini‐Rousseau et al (2022) (published after our study search), medulloblastoma was diagnosed before the age of three in all patients except five (5.8% of cohort), aged respectively 3.3, 3.4, 3.8, 4, and 5.8 years (Guerrini‐Rousseau et al, 2022). We also show that every patient with a diagnosis of medulloblastoma presented with clinical symptoms and not one patient in the literature was undergoing medulloblastoma surveillance imaging.…”

Section: Discussionmentioning

confidence: 86%

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

Lee,

Evans,

Stephen

et al. 2024

American J of Med Genetics Pt A

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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.

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Section: Discussionmentioning

confidence: 86%

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

Lee,

Evans,

Stephen

et al. 2024

American J of Med Genetics Pt A

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“…Homozygous SUFU variants cause Joubert syndrome, while heterozygous variants pose risks of medulloblastoma in childhood, gonadal tumors in adolescence, and BCC, Gorlin syndrome, and meningiomas in adulthood [12][13][14]. A similar variant at the same position and splice site of the SUFU gene [c.183-2A > C (NM_016169.4)] has been previously reported in a case with Gorlin syndrome and medulloblastoma in ClinVar (RCV001990795.2) [12,19].…”

Section: Discussionmentioning

confidence: 91%

“…Inactivation of SUFU unleashes control of GLI1 transcription factors, promoting tumorigenesis in various cancers [10,11]. Homozygous SUFU variants cause Joubert syndrome, while heterozygous variants pose risks of medulloblastoma in childhood, gonadal tumors in adolescence, and BCC, Gorlin syndrome, and meningiomas in adulthood [12][13][14]. In recent studies, SUFU is a crucial link between the Hh and WNT pathways, interacting with SPOP and PTEN in clear renal cell carcinoma pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

SUFU: A potential novel gene responsible for Lhermitte Duclos disease

Güngör,

Solmaz,

Karaca

et al. 2024

Preprint

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Lhermitte-Duclos disease (LDD) is a rare dysplastic gangliocytoma of the cerebellum, typically presenting as a hamartomatous lesion in the posterior fossa. PTEN and the PI3K/AKT/mTOR pathway are involved in the pathogenesis of LDD. We present a case of a patient who incidentally was detected with LDD. A novel, pathogenic, heterozygous, de novo, splice site variant c.183-2A > G (NM_016169.4) in the SUFU gene was identified with targeted next-generation sequencing from genomic DNA. SUFU, a tumor suppressor gene, negatively regulates the hedgehog (Hh) signaling pathway. SUFU also influences WNT and PTEN/AKT/mTOR signaling pathways. While SUFU pathogenic variants are associated with various central nervous system (CNS) tumors, this is the first reported link between SUFU and LDD. The study delves into the role of SUFU in LDD development, establishing the novel SUFU variant as a potential genetic marker for the disease. Sanger sequencing and gel electrophoresis were applied to RNA isolated from blood to show that the variant disrupts splicing. DNA extracted from tumor tissue underwent NGS with the TWIST Exome 2.0 Panel. Results unveiled the de novo pathogenic SUFU (c.183-2A > G) and PTEN (c.389G > A) variants. In conclusion, this study establishes the first reported association between LDD and a germline, de novo SUFU variant, and sheds light on the crucial role of SUFU in LDD pathogenesis. It contributes to the broader understanding of genetic factors influencing this rare cerebellar disorder.

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“…Germline mutations in known tumor suppressor SUFU on chromosome 10 have long been associated with childhood medulloblastoma, with loss of SUFU leading to disruptions in the sonic hedgehog signaling pathway ( 24 , 25 ). Germline disruptions in SUFU are also thought to predispose to development of additional cancers such as basal cell carcinoma, gonadal tumors, and meningiomas ( 26 ). Mutations in SUFU have been linked to development of isolated familial meningiomas and development of multiple meningiomas ( 27 ).…”

Section: Key Genetic Changes In Meningiomasmentioning

confidence: 99%

Recent advances in the molecular prognostication of meningiomas

Wang

Haddad²,

Young³

et al. 2023

Front. Oncol.

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Meningiomas are the most common primary intracranial neoplasm. While traditionally viewed as benign, meningiomas are associated with significant patient morbidity, and certain meningioma subgroups display more aggressive and malignant behavior with higher rates of recurrence. Historically, the risk stratification of meningioma recurrence has been primarily associated with the World Health Organization histopathological grade and surgical extent of resection. However, a growing body of literature has highlighted the value of utilizing molecular characteristics to assess meningioma aggressiveness and recurrence risk. In this review, we discuss preclinical and clinical evidence surrounding the use of molecular classification schemes for meningioma prognostication. We also highlight how molecular data may inform meningioma treatment strategies and future directions.

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Cancer risk and tumour spectrum in 172 patients with a germlineSUFUpathogenic variation: a collaborative study of the SIOPE Host Genome Working Group

Cited by 9 publications

References 44 publications

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

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

SUFU: A potential novel gene responsible for Lhermitte Duclos disease

Recent advances in the molecular prognostication of meningiomas

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