Showing papers by "Huib N. Caron published in 2008"

Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

Abstract: Background: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions: The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.

Prevalence and patterns of morphological abnormalities in patients with childhood cancer.

Abstract: Context Constitutional gene defects predispose to cancer in children. Such tumor predisposition syndromes can be recognized by specific patterns of morphological abnormalities. ObjectivesTo assess the prevalence of morphological abnormalities in a large cohort of patients with childhood cancer and to identify new tumor predisposition syndromes.Design, Setting, and Participants Patients were recruited from Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands, between January 2000 and March 2003. A total of 1073 patients underwent a physical examination directed at 683 morphological abnormalities. The patient cohort consisted of 898 long-term survivors of childhood cancer and 175 newly diagnosed pediatric patients with cancer. The control group consisted of 1007 schoolchildren examined in an identical way. Mean ages of patients and controls were 21.2 and 10.4 years, respectively. Main Outcome MeasuresPrevalence and patterns of morphological abnormalities in patients compared with controls. To prevent age bias, only age-independent abnormalities were used for overall prevalence analysis. Patients younger than 9 years were excluded from the pattern analysis. The sample was restricted to white patients to prevent ethnicity bias.Results Morphological abnormalities were significantly more prevalent in pediatric patients with cancer. Major abnormalities were present in 26.8% of patients vs 15.5% of controls (P < .001) and minor anomalies in 65.1% of patients vs 56.2% of controls (P < .001). Three or more minor anomalies were detected in 15.2% of patients vs 8.3% in controls (P < .001). Forty-two patients were diagnosed with an established tumor predisposition syndrome. Multivariate analyses showed 14 morphological abnormalities to occur significantly more often in the patient group. For 2 of these (blepharophimosis and asymmetric lower limbs), we identified statistically significant patterns of co-occurring morphological abnormalities suggestive of new tumor predisposition syndromes. Thirty-four patients fit 1 of the 2 novel tumor predisposition patterns. ConclusionsPediatric patients with cancer show a significantly higher prevalence of morphological abnormalities compared with controls. Specific patterns of morphological abnormalities indicate possible unrecognized tumor predisposition syndromes, but validation in an independent sample is needed.

Longitudinal assessment of health-related quality of life in preschool children with non-CNS cancer after the end of successful treatment

Abstract: Background. The aim of the study was to access Health Related Quality of Life (HRQoL) in preschool cancer survivors during the first 3 years of continuous remission after the end of successful treatment, and to identify predictors of HRQoL. Procedure. Parent-reported HRQoL was assessed in 53 preschool children treated successfully for cancer, using the TAPQOL and compared with norm data. Longitudinal mixed models analyses were performed to investigate to what extent demographic and medical variables and parental psychological distress were predictive of HRQoL over time. Results. Two months after the end of successful cancer treatment, survivors showed significantly (P < 0.01) more problem behavior and anxiety, and scored significantly worse (P < 0.01) on sleeping, motor functioning, positive mood and liveliness than the norm. One year after the end of treatment survivors still showed significantly (P < 0.01) more anxiety and worse motor functioning. The level of HRQoL in survivors had normalized 2 and 3 years after the end of treatment. Longer duration of treatment, bad prognosis and greater parental psychological distress were associated with worse scores on the Physical Component Score of the TAPQOL. Medical variables and parental psychological distress were not associated with the Mental Component Score. Conclusions. Survivors adjusted well to the cancer experience and HRQoL improved with time. Despite overall resilience in survivors over time, physical as well as psychosocial monitoring in follow-up is recommended. Standard aftercare should preferably include psychosocial screening, education, and counseling directed at both survivors and parents. Pediatr Blood Cancer 2008;50:1047‐1051. 2007 Wiley-Liss, Inc.