Jane E. Skeen

A gene expression signature for relapse of primary wilms tumors

Anaplastic histology and metastasis are each associated with higher relapse and mortality rates in Wilms tumor patients. However, not all anaplastic tumors relapse and some nonanaplastic tumors relapse unexpectedly. To identify more accurate early prognostic indicators, we analyzed expression of 4,900 cancer-related genes in 26 primary Wilms tumors. This analysis revealed that expression of a set of four genes predicts future relapse of primary Wilms tumors with high accuracy, independent of anaplasia. Random permutation testing of this prognostic gene expression signature yielded P = 0.003. Real-time reverse transcription-PCR analysis of the four genes in an independent primary tumor set resulted in correct prediction of future relapse with an accuracy of 92%. One of the four genes in the prognostic signature, CCAAT/enhancer binding protein beta (C/EBPB), is expressed at higher levels in both primary relapsing tumors and metastatic tumors than in primary nonrelapsing tumors. Short interfering RNA-mediated down-regulation of C/EBPB expression in WiT49, a cell line derived from a metastatic Wilms tumor, resulted in spontaneous apoptosis. These findings suggest that C/EBPB is a critical survival factor for Wilms tumor cells and that its expression contributes to the prognosis of Wilms tumor patients.

Childhood cancer among the polynesian population

From June 1981 through June 1989, 95 Polynesian children were seen for initial care of malignancy at the Princess Mary Hospital for Children (PMHC). The incidence of malignancy in the Polynesian populations served, the histology of the malignancies, and the outcome of therapy were reviewed and compared with 185 non‐Polynesian (non‐P) patients seen during the same period. Incidence figures for Polynesians and non‐P were similar, but histologic patterns differed, showing an increased occurrence of leukemia, particularly nonlymphoblastic leukemia, an increased occurrence of bone tumors, and a decreased incidence of central nervous system tumors for Polynesians. Survival for Polynesian children with acute lymphoblastic leukemia was worse than for non‐P. Survival in all other disease categories was similar.

Transition of childhood cancer survivors to adult care: The survivor perspective

To the Editor: We read with interest Kenney and colleagues’1 study examining practices and perceived barriers to transition for childhood cancer survivors among US pediatric oncologists. Ninety-six percent of pediatric oncologists reported caring for survivors up to 21 years. Systematic approaches to transition were lacking. Oncologists reported patients’ age, presence of adult comorbidities, and pregnancy were reasons to transfer to adult care. Oncologists expressed concern over patients with complex medical, cognitive or psychosocial issues. Our ongoing study of survivors >5 years post treatment, in Australia and New Zealand provides additional useful data. Survivors (N = 295, mean age = 26.3, SD = 7.7years; mean time since treatment = 17.0, SD = 8.3years) and parents of survivors <16 years (N = 173, child mean age = 13.5, SD = 3.9years; mean time since treatment = 9.0 SD = 3.7years) completed questionnaires relating to transition. Eighteen years of age was the most commonly preferred age for transition nominated by survivors (38.9%) and parents (49.2%), followed by 21-years (survivors: 23.2%, parents: 25.9%). Given the choice, some survivors may be reluctant to transition out of pediatric-based follow-up. Preferred age for transition differed between survivors and parents (χ2 = 14.34, p = .006). More survivors reported preferring never to transition out of specialised follow-up care (10.5%), compared to parents (7.6%). Our results show few clinical factors, or number of health concerns, were associated with preferred transition age, in contrast to pediatric oncologists’ reasons for transition.1 Cancer type and stage were not associated with preferred age for transition. Survivors who received radiotherapy were more likely to report a preference for never transitioning (12.4%), compared with those who did not have radiotherapy (6.7%; χ2 = 12.916, p = .012). No other treatment variables, or current health concerns, were associated with preferred transition age. Survivors who had recently completed treatment were more likely to prefer an older age for transition or never leaving pediatric specialised follow-up care (F(4,493) = 8.358, p < .001). Survivors’ current age was associated with preferred age of transition (F(4,548) = 7.822, p < .001); for example survivors reporting a preference for never leaving pediatric specialised follow-up care were on average 25 years (SD = 6.7), while those reporting 16 years old was appropriate for transition were on average 28.7 years (SD = 9.4). Survivors currently attending a survivorship clinic more commonly preferred to never transition (12.6%) compared with those not attending clinic (6.1%; χ2 = 9.671, p = 0.046). Never transitioning (10.4%) or 21years of age (25.2%) were more commonly reported as the preferred transition age for survivors perceiving a higher risk of late effects (χ2 = 11.796, p = .019) and greater worry (χ2 = 10.123, p = 0.038) compared with those who did not report any perceived risk or worry (5.4%, 14.9% respectively). In Australia and New Zealand, pediatric-based survivorship care rarely extends beyond 24 years of age.2 Our results suggest survivors currently facing transition, due to their age and availability of care, may prefer to remain in specialised follow-up care. Successful transition requires that survivors are informed about their cancer, their treatment, and crucially, their risk of late effects and second cancers.3,4 Survivors’ lack of knowledge about their risk, and worry about late effects may impede successful transition to adult care.5 Development of formalized transition programs may overcome these barriers to transition.1,6

Models of Care for Survivors of Childhood Cancer From Across the Globe: Advancing Survivorship Care in the Next Decade

With improvements in cancer treatment and supportive care, a growing population of survivors of childhood cancer at risk for significant and potentially life-threatening late effects has been identified. To provide a current snapshot of the models of care from countries with varying levels of resources and health care systems, stakeholders in childhood cancer survivorship clinical care and research were identified from 18 countries across five continents. Stakeholders responded to a survey and provided a brief narrative regarding the current state of survivorship care. Findings indicate that among pediatric-age survivors of childhood cancer (allowing for differences in age cutoffs across countries), resources are generally available, and a large proportion of survivors are seen by a physician familiar with late effects in most countries. After survivors transition to adulthood, only a minority are seen by a physician familiar with late effects. Despite the need to improve communication between pediatric oncology and primary care, only a few countries have existing national efforts to educate primary care physicians, although many more reported that educational programs are in development. These data highlight common challenges and potential solutions for the lifelong care of survivors of childhood cancer. Combining risk-based and patient-oriented solutions for this population is likely to benefit both providers and patients.

Germline mutations and somatic inactivation of TRIM28 in Wilms tumour

Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.

Childhood cancer registration in New Zealand: A registry collaboration to assess and improve data quality

AIM To evaluate the completeness and accuracy of child cancer registration in New Zealand. METHODS Registrations for children aged 0-14 diagnosed between 1/1/2010 and 31/12/2014 were obtained from the New Zealand Cancer Registry (NZCR) and the New Zealand Childrens Cancer Registry (NZCCR). Six key data fields were matched using National Health Index numbers in order to identify and resolve registration discrepancies. Capture-recapture methods were used to assess the completeness of cancer registration. RESULTS 794 unique cases were reported; 718 from the NZCR, 721 from the NZCCR and 643 from both registries. 27 invalid cancer registrations were identified, including 19 residents of the Pacific Islands who had travelled to New Zealand for treatment. The NZCCR provided 55 non-malignant central nervous system tumour and 16 Langerhans cell histiocytosis cases which were not registered by the NZCR. The NZCR alerted the NZCCR to 18 cases missed due to human error and 23 cases that had not been referred to the specialist paediatric oncology centres. 762 cases were verified as true incident cases, an incidence rate of 166.8 per million. Registration accuracy for six key data fields was 98.6%. According to their respective inclusion criteria case completeness was 99.3% for the NZCR and 94.4% for the NZCCR. For childhood malignancies covered by both registries, capture-recapture methods estimated case ascertainment at greater than 99.9%. CONCLUSION With two national registries covering childhood cancers, New Zealand is uniquely positioned to undertake regular cooperative activities to ensure high quality data is available for research and patient care.