Intracranial Neoplasms in the First Year of Life: Results of a Third Cohort of Patients From a Single Institution

Toescu, Sebastian; James, Greg; Phipps, Kim; Jeelani, Owase; Thompson, Dominic; Hayward, Richard; Aquilina, Kristian

doi:10.1093/neuros/nyy081

Cited by 19 publications

(10 citation statements)

References 29 publications

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“…The expanded upper roof plate in Lcre;Ptch cko ;NICD1 mice is consistent with the developmental origin and cilia defect of CPC being driven by NOTCH and SHH signaling. These animals represent an ideal therapeutic model for congenital or infantile CPC, a rare condition associated with high morbidity and mortality [ 50 , 51 ]. Indeed, NOTCH inhibition by IMR-1 rescued the cilia deficit by inducing multiciliated tumor cells, whereas SHH pathway inhibitors suppressed tumor cell proliferation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

Han

Singh

et al. 2022

Cell Death Differ

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Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC.

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Section: Discussionmentioning

confidence: 99%

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

Han

Singh

et al. 2022

Cell Death Differ

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“…The enlarged roof plate in Lcre;Ptch cko ; NICD1 animals is consistent with the developmental origin and cilia defect of CPC driven by NOTCH and SHH signaling. These animals serve as ideal therapeutic models for congenital or infantile CP tumors, a rare condition associated with high morbidity and mortality (Crawford and Isaacs 2019; Toescu et al 2019). Indeed, NOTCH inhibition by IMR-1 rescued the cilia deficit by forming multiple cilia and decreasing mitosis in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

GEMC1-MCIDAS transcriptional program regulates multiciliogenesis in the choroid plexus and acts as a barrier to tumorigenesis

Han

Singh

et al. 2020

Preprint

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Multiciliated cells (MCCs) in the brain include the ependymal cells and choroid plexus (CP) epithelial cells. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. However, the mechanisms and functional significance of multiciliogenesis in the CP remain unknown. Deregulated oncogenic signals cause CP carcinoma (CPC), a rare but aggressive pediatric brain cancer. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. NOTCH-driven CP tumors were monociliated, whereas disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of GEMC1 and MCIDAS, early regulators of multiciliogenesis. Consistently, GEMC1-MCIDAS function is essential for multiciliation in the CP, and is critical for correcting multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia. Consistently, CPC driven by deletion of Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal a GEMC1-MCIDAS multiciliation program in the CP critical for inhibiting tumorigenesis, and it may have therapeutic implications for the treatment of CPC.

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“…However, the prognosis of patients with central nervous system tumors was markedly different in our study. Toescu et al 12 reported that choroid plexus papilloma occurred within 1 year of age, followed by low‐grade glioma with a mortality rate of 0%, which required multiple operations. Intracranial primitive neuroectodermal tumors had a 5‐year survival rate of 0%.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and treatment of infantile malignant solid tumors in beijing, China: A multicenter 10‐year retrospective study

Jin

Zhi

Xie

et al. 2020

Pediatric Investigation

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Importance Cancer is the main cause of death by disease in children. Children experience the highest incidence of cancer in the first year of life. However, there is no comprehensive registration system for children with tumors in China. Objective To summarize the diagnosis and treatment of infant cancer and analyze the status of standardized diagnosis and management among several treatment centers in Beijing, China, thereby providing evidence to guide further clinical research. Methods From January 1, 2010 to December 31, 2019, patients with newly diagnosed infantile malignant solid tumors were admitted to six large tertiary pediatric solid tumor diagnosis and treatment centers in Beijing. The epidemiology, clinical features, and therapeutic effects of tumors in these patients were analyzed retrospectively. All patients were followed up until March 31, 2020. Results In total, 938 patients were enrolled in this study. There were 530 boys (56.5%) and 408 girls (43.5%); the median age was 6.0 months (range, 0–12.0 months). The three most common tumors were retinoblastoma in 366 patients (39.0%), neuroblastoma in 266 patients (28.4%), hepatoblastoma in 133 patients (14.2%), and central nervous system tumors in 52 patients (5.5%). The estimated 5‐year overall survival rate was 81.3% ± 1.8%, and the 5‐year event‐free survival rate was 71.8% ± 2.9%. The 5‐year overall survival rates of non‐rhabdomyosarcoma soft tissue sarcoma, neuroblastoma, and retinoblastoma were 100%, 88% ± 2.2%, and 86.9% ±2.1%, respectively. The 5‐year event‐free survival rates were 81.1% ± 2.7% for neuroblastoma, 81.6% ± 9.8% for non‐rhabdomyosarcoma soft tissue sarcoma, and 72.7% ± 14.1% for extracranial malignant germ cell tumors. Interpretation The three most common infantile malignant solid tumors were retinoblastoma, neuroblastoma, and hepatoblastoma. Multidisciplinary combined diagnosis and treatment is needed for infantile tumors.

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Intracranial Neoplasms in the First Year of Life: Results of a Third Cohort of Patients From a Single Institution

Abstract: Overall survival from neonatal brain tumors remains similar to previous series; analysis of tumor subtypes reveals improvements for CPP and gliomas. Despite increasing operative intervention, operative mortality continues to decline for this group of challenging patients.

Cited by 19 publications

References 29 publications

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

GEMC1-MCIDAS transcriptional program regulates multiciliogenesis in the choroid plexus and acts as a barrier to tumorigenesis

Diagnosis and treatment of infantile malignant solid tumors in beijing, China: A multicenter 10‐year retrospective study

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