Germline <i>SUFU</i> mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis

Guerrini-Rousseau, Léa; Dufour, Christelle; Varlet, Pascale; Masliah‐Planchon, Julien; Bourdeaut, Franck; Guillaud‐Bataille, Marine; Abbas, Rachid; Bertozzi, Anne Isabelle; Fouyssac, Fanny; Huybrechts, Sophie; Puget, Stéphanie; Paillerets, Brigitte Bressac-de; Caron, Olivier; Sévenet, Nicolas; Dimaria, Marina; Villebasse, Sophie; Delattre, Olivier; Valteau‐Couanet, Dominique; Grill, Jacques; Brugières, Laurence

doi:10.1093/neuonc/nox228

Cited by 56 publications

(57 citation statements)

References 52 publications

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“…Mutations in the intracellular components, SUFU and GLI2, are also frequently found in human SHH MB. SUFU alterations include broad and focal deletions and point mutations (Brugiè res et al, 2010(Brugiè res et al, , 2012Guerrini-Rousseau et al, 2017;Kool et al, 2014;Slade et al, 2011;Taylor et al, 2002). These alterations are believed to cause elevated GLI activity, thereby inducing MB tumorigenesis.…”

Section: Data Resources Gse112699 Gse112772 Gse112702mentioning

confidence: 99%

“…It is critical to elucidate the function of SUFU in SHH MB because patients with germline SUFU mutations have worse survival compared with the usually good prognosis of SHH MB. Furthermore, these MBs are non-responsive to SMO inhibitors, which are the only targeted treatment available for SHH MB (Guerrini-Rousseau et al, 2017;Kool et al, 2014). Therefore, it is important to characterize and generate faithful mouse models of SHH MB driven by alterations downstream of SMO to help devise targeted therapeutic treatments.…”

Section: Data Resources Gse112699 Gse112772 Gse112702mentioning

confidence: 99%

“…Since focal and broad losses of SUFU were found in human SHH MBs (Brugiè res et al, 2010(Brugiè res et al, , 2012Guerrini-Rousseau et al, 2017;Kool et al, 2014;Slade et al, 2011;Taylor et al, 2002), we aimed to generate a clinically relevant Sufu mutant mouse model of MB. First, we employed a cohort of wild-type, Sufu +/À , and Ptch1 +/À mice and monitored for up to 1 year of age for spontaneous MB tumorigenesis.…”

Section: Loss Of Sufu Alone Is Insufficient To Drive Mb Formationmentioning

confidence: 99%

“…SUFU has long been implicated as a tumor suppressor in SHH MBs. Genomic sequencing of SHH MBs has identified somatic and germline, focal and broad losses of SUFU, as well as point mutations causing frameshift or uncharacterized functional changes, particularly enriched in children younger than 3 years of age (Brugiè res et al, 2010(Brugiè res et al, , 2012Guerrini-Rousseau et al, 2017;Kool et al, 2014;Slade et al, 2011;Taylor et al, 2002). Previous attempts at characterizing the role of SUFU in SHH MBs found that Sufu +/À mice are not prone to MBs, and only simultaneous loss of Trp53 could induce tumor formation (Lee et al, 2007;Sv€ ard et al, 2006).…”

Section: Sufu Exerts Dual Functions In Shh Mb Tumorigenesismentioning

confidence: 99%

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Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Yin

Satkunendran

et al. 2019

Developmental Cell

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Graphical Abstract Highlights d Sufu exerts tumor-promoting and -suppressive functions in SHH medulloblastoma d Sufu;Spop double knockout medulloblastoma mouse model unveils GLI2 targetome d ATOH1 and GLI2 cooperate to activate target genes in SHH medulloblastoma SUMMARY SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB ($60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis. (C) Survival is normal in Sufu KO mice, while Ptch1 KO mice rapidly succumb to MBs. (D) Gene expression profiling by cDNA microarray reveals downregulation of several Gli target genes and moderate expression of some Hh pathway components and MB signature genes in Sufu KO cerebellum at P13, while Ptch1 KO MBs displays upregulation of Hh component genes and full-blown MB signature. See also Figure S1.

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Section: Data Resources Gse112699 Gse112772 Gse112702mentioning

confidence: 99%

Section: Data Resources Gse112699 Gse112772 Gse112702mentioning

confidence: 99%

Section: Loss Of Sufu Alone Is Insufficient To Drive Mb Formationmentioning

confidence: 99%

Section: Sufu Exerts Dual Functions In Shh Mb Tumorigenesismentioning

confidence: 99%

See 2 more Smart Citations

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Yin

Satkunendran

et al. 2019

Developmental Cell

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“…We hypothesized that the effects of germline variants on cancer progression may be strong enough to identify associations with patient outcome. Previous studies tested for an association between patient outcome and a small number of germline variants in genes wellcharacterized in a given cancer [28,29]. We published an unbiased method of testing for an association between a large number of germline variants and patient outcome in patients with lower-grade gliomas [30].…”

Section: Introductionmentioning

confidence: 99%

The pan-cancer landscape of prognostic germline variants in 10,582 patients

et al. 2020

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Background: While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. Methods: We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. Results: We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. Conclusions: Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.

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Gorlin Syndrome

Farndon¹,

Evans²

2020

Cassidy and Allanson's Management of Genetic Syndromes

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Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis

Cited by 56 publications

References 52 publications

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

The pan-cancer landscape of prognostic germline variants in 10,582 patients

Gorlin Syndrome

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