Principles of tumorigenesis and emerging molecular drivers of <scp>SHH</scp>‐activated medulloblastomas

Menyhárt, Otília; Győrffy, Balázs

doi:10.1002/acn3.762

Cited by 24 publications

(15 citation statements)

References 119 publications

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“…Our results suggest that rare heterozygous variants in POLR3A may lead to different degrees of recessive phenotype in patients through dose-effect models. Due to the ‘gate keeper’ role of SUFU in sonic hedgehog pathway, mutations in the SUFU gene were mostly studied in the context of susceptible tumor diseases ( 37 ). As far as we know, this is the first time that this gene is reported to be related to GHD.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

Xie

Zhao

et al. 2021

Front. Endocrinol.

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PurposeCongenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis.MethodsWe retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.ResultsIn 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients.ConclusionOur study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

Xie

Zhao

et al. 2021

Front. Endocrinol.

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“…Like BCCs, most Shh-medulloblastomas are characterized by mutations in the PTCH1 gene, and to a smaller extent, in SUFU and SMO genes [ 196 ]. Likewise, Shh-medulloblastomas are also amenable to SMO inhibitor treatment; in particular, sonidegib has shown superior antitumor efficacy (ORR: 55%) compared to vismodegib (ORR: 17%) in a systemic review and meta-analysis of phase I and phase II clinical trials of pediatric and adult medulloblastoma patients treated with sonidegib and vismodegib [ 197 ].…”

Section: Hh Pathway As Therapeutic Targets In Cancer Clinical Studiesmentioning

confidence: 99%

The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

et al. 2021

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The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

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“…The current treatment approach includes risk-adapted RT and four cycles of cyclophosphamide-based, dose-intensive chemotherapy (incorporating cisplatin, vincristine, and cyclophosphamide), followed by stem cell or bone marrow rescue. This regimen produced 85% 5-year survival (95% CI [75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94] in the average-risk MB population and 70% 5-year survival (95% 54-84) in the high-risk population [21]. Histological subtype also correlated with 5-year event-free survival and was lowest (57%) for large cell anaplastic tumors [21].…”

Section: Chemotherapymentioning

confidence: 99%

“…Mutations of some genes are almost exclusively specific to the adult subgroup, including TERT promoter mutations that drive telomerase activity [76] or recurrent mutations of the PI3K/AKT/mTOR pathway [68]. Additional subgroup-specific molecular alterations affect chromatin modulation, histone acetyltransferase, or nuclear receptor corepressor complexes [77]. High expression often cannot be traced to specific mutations or chromosome aberrations; like in the case of cMET that is among the most frequently hypo-or hypermethylated genes in MBs [78].…”

Section: Shh-activated Mbsmentioning

confidence: 99%

“…Moreover, SMO inhibition hinders normal bone and teeth development in pediatric patients causing growth plate fusions that persist long after therapy cessation [88]. Preclinical efforts seeking targeted therapies against SHH-MBs also focus at epigenetic treatments with BET bromodomain inhibitors, inhibition of the G2/M regulators AURK and PLK, cMET inhibitors, strategies targeting stemlike cells, and interventions utilizing immunotherapies [77].…”

Section: Shh-activated Mbsmentioning

confidence: 99%

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Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

Menyhárt

Győrffy

2020

Cancer Metastasis Rev

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Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNTactivated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio-and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CART therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.

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Principles of tumorigenesis and emerging molecular drivers of SHH‐activated medulloblastomas

Cited by 24 publications

References 119 publications

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

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