Pineoblastoma in a child with 22q11.2 deletion syndrome

Nguyen, Linda; Crawford, John R.

doi:10.1136/bcr-2018-226434

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…Furthermore, DGCR8 alterations, seen in high-risk nephroblastomas, were previously unreported in PBs [44]. Involvement of DGCR8 (DiGeorge syndrome critical region 8) in our molecular cohort consolidates the oncogenic role of disrupted miRNA processing and provides an explanation for the rare association between DiGeorge syndrome and PB [24,36]. Despite the incomplete evaluation of cancer predisposition in this cohort, the presence of germline DICER1 mutation or 22q11.2 deletion in at least 9% of our patients older than three years highlights the importance of genetic assessment beyond germline RB1 mutations in patients with PB.…”

Section: Discussionsupporting

confidence: 58%

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

et al. 2019

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Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with highdose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥3 years; SJYC07 for patients <3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03=30; SJYC07=12; non-protocol=16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk=23.4 Gy, high-risk=36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n=43), whole-exome sequencing (n=26), and RNA-sequencing (n=16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5±10.3% (P=0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3±13.2% and 0% (P=0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNAmethylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene.Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.Liu et al.

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Section: Discussionsupporting

confidence: 58%

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

et al. 2019

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“…Interestingly, one group 1 PB (RBTC757) exhibited loss of chr 22 copy in the context of the chr 22q11.2 deletion syndrome (22q11.2DS, DiGeorge syndrome). The minimal chr 22q11.2DS region which encompasses DGCR8 has also been linked to two prior cases of PB [46,61,34], and suggest DGCR8 loss may predispose to PB.…”

Section: Discussionmentioning

confidence: 92%

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study

Vasiljevic

Dufour

et al. 2019

Acta Neuropathol

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Pineoblastoma (PB) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular subgroups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinicopathologic significance of each subgroup. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss of function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC subgroup, respectively characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age <3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibit substantial molecular heterogeneity with sub-group associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

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“…Although 22q11.2DS may increase risk for particular malignancies,1–3 few reports have documented brain tumours in 22q11.2DS 1 4 5. The low population prevalence of brain tumours6 encourages suggestion that 22q11.2DS pathology facilitated the development of the tumours in our patient.…”

Section: Descriptionmentioning

confidence: 67%

Coincident pineocytoma and probable brainstem glioma in a child with 22q11.2 deletion syndrome

et al. 2022

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Pineoblastoma in a child with 22q11.2 deletion syndrome

Cited by 3 publications

References 3 publications

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study

Coincident pineocytoma and probable brainstem glioma in a child with 22q11.2 deletion syndrome

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