Anne-Isabelle Bertozzi

Factors related to pregnancy and birth and the risk of childhood brain tumours: The ESTELLE and ESCALE studies (SFCE, France).

Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether maternal preconceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population‐based case‐control studies with similar designs conducted in 2003–2004 and 2010–2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of preconceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more; OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population‐based studies may provide further insight into findings by CBT subtypes.

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

Background Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.

Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE)

Some previous epidemiological studies have suggested that pesticide exposure during pregnancy may have a possible role in the development of childhood brain tumors (CBT). We pooled data from two French national population‐based, case–control studies to investigate the association between maternal residential use of pesticides during pregnancy and the risk of CBT. The mothers of 437 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency‐matched by age and gender, answered a structured telephone interview conducted by trained interviewers. Unconditional logistic regression was used to estimate pooled odds ratio (OR) and 95% confidence intervals (95% CI). CBT was significantly associated with the maternal home use of pesticides during pregnancy (OR 1.4, 95% CI 1.2–1.8) and, more specifically, with insecticide (OR 1.4, 1.2–1.8). We could not draw any conclusions about herbicides and/or fungicides because few women used them during pregnancy and most of these mothers also used insecticides. Although potential recall bias cannot be excluded, our findings of this pooled analysis support the hypothesis that residential maternal use of pesticides during pregnancy and particularly insecticides may increase the risk of CBT. Future investigations to verify these findings and to explore for CBT subtypes and dose–response are necessary to have a better understanding of the possible role of pesticides in etiology of CBT.

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013

PURPOSE The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma. METHODS AND MATERIALS Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy. RESULTS Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival. CONCLUSIONS We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.

Childhood brain tumours, early infections and immune stimulation: A pooled analysis of the ESCALE and ESTELLE case-control studies (SFCE, France)

BACKGROUND Few studies have investigated whether early infections and factors potentially related to early immune stimulation might be involved in the aetiology of childhood brain tumours (CBT). In this study, we investigated the associations between CBT with early day-care attendance, history of early common infections, atopic conditions (asthma/wheezing, eczema, allergic rhinitis), early farm residence/visits and contact with animals. METHODS We pooled data from two nationwide French case-control studies, the ESCALE and ESTELLE studies. Children with a CBT diagnosed between 1 and 14 years of age were identified directly from the French National Registry of Childhood Cancers, while population controls were recruited from telephone subscribers. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression adjusted for potential confounders. RESULTS The analyses included 469 cases and 2719 controls. We found no association between attending a day-care centre (OR: 0.9, 95%CI: 0.7-1.2) or having had repeated common infections (OR: 0.9, 95%CI: 0.7-1.2) in the first year of life and the risk of CBT. There was also no association with a history of asthma/wheezing (OR: 0.8, 95%CI: 0.56-1.1). Farm visits (OR: 0.6, 95%CI: 0.5-0.8) as well as contact with pets (OR: 0.8, 95%CI: 0.6-1.0) in the first year of life were inversely associated with CBT. CONCLUSIONS Our findings suggest a protective effect of early farm visits and contact with pets, but not with other markers of early immune stimulation. This might be related to immune stimulation but needs further investigation.

EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity: EWSR1-PATZ1 gene fusion

We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.