Diana S. Osorio

Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.

SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature

IntroductionIndividuals with Down syndrome (DS) have an increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model, DS is associated with cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granule cell layer (EGL). Treatment of these mice with sonic hedgehog signaling pathway (Shh) agonists promote normalization of CGNPs and improved cognitive functioning.Case reportWe describe a 21-month-old male with DS and concurrent desmoplastic/nodular medulloblastoma (DNMB)—a tumor derived from Shh dysregulation and over-activation of CGNPs. Molecular profiling further classified the tumor into the new consensus SHH molecular subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway.DiscussionThe developmental failure of CGNPs in DS patients offers a plausible explanation for the rarity of medulloblastoma in this population. Conversely, patients with PTCH1 germline mutations experience Shh overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation. This represents the first documented report of an individual with DS simultaneously carrying PTCH1 germline mutation.ConclusionWe have observed a highly unusual circumstance in which the PTCH1 mutation appears to “trump” the effects of DS in causation of Shh-activated medulloblastoma.

Tandem thiotepa with autologous hematopoietic cell rescue in patients with recurrent, refractory, or poor prognosis solid tumor malignancies

Background: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high‐dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high‐dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. Procedure: Thiotepa was administered intravenously at a dose of 200 mg/m2/day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. Results: Fifty‐eight patients received 96 courses. Thirty‐eight (65%) patients received two courses of therapy. Twenty‐seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68–103 months following AHCR. Conclusions: Two cycles of high‐dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.

Increased Prevalence of Congenital Heart Disease in Children With Diamond Blackfan Anemia Suggests Unrecognized Diamond Blackfan Anemia as a Cause of Congenital Heart Disease in the General Population: A Report of the Diamond Blackfan Anemia Registry

Congenital heart disease (CHD) is one of the most commonly occurring congenital anomalies in the general population. In patients with Diamond Blackfan anemia (DBA)—a rare inherited bone marrow failure syndrome—CHD represents ≈30% of all congenital anomalies.1 Affected individuals within multiplex families may have hematologic manifestations with or without CHD or have CHD alone. To support a link between these 2 conditions, we hypothesized that because CHD is common in the Diamond Blackfan Anemia Registry (DBAR) cohort, there are patients with occult DBA in the general CHD population. This study could reveal new knowledge regarding the pathogenesis of nonsyndromic CHD. DBA, characterized by hypoproliferative, proapoptotic erythropoiesis and red cell failure, birth defects, growth failure, and cancer predisposition, presents with hypoplastic anemia; median age, 2 months. Inactivating mutations in large or small subunit-associated RP (ribosomal protein) genes are found in 65% to 70% of cases. RP-associated DBA has autosomal dominant inheritance with variable penetrance or presents as sporadic new dominant mutations. A few cases are not RP associated.1,2 The DBAR of North America, established in 1991, captures patients in a nonbiased fashion.1 In the DBAR (n=744), 111 patients have CHD, representing a significantly greater prevalence of CHD in patients with DBA (n=111 of 744; prevalence, 1491.9/10 000; 14.9%) compared with the general population3 (n=3240 of 398 140; prevalence, 81.4/10 000; <1%; P <0.0001 [χ2]). The relative distribution of CHD in DBA is similar to the general population (Figure). Figure. Congenital heart disease (CHD) in Diamond Blackfan anemia (DBA). A , The CHD anomalies in the Diamond Blackfan …