Research priorities for children's cancer: a James Lind Alliance Priority Setting Partnership in the UK.

OBJECTIVES: To engage children who have experienced cancer, childhood cancer survivors, their families and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities. PARTICIPANTS: Children and survivors of childhood cancer, diagnosed before age 16, their families, friends and professionals who work with this population. RESULTS: Four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; 4 were already answered and 3 were under active study, therefore, removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children's surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was 'can we find effective and kinder (less burdensome, more tolerable, with fewer short and long-term effects) treatments for children with cancer, including relapsed cancer?' CONCLUSIONS: We have identified research priorities for children's cancer from the perspectives of children, survivors, their families and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research.

Stratification of Wilms tumor by genetic and epigenetic analysis.

Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.

Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study.

BACKGROUND: Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the child's developing nervous system at a crucial time-with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma. METHODS: Between December, 1992, and April, 2003, we enrolled 89 children with ependymoma who were aged 3 years or younger at diagnosis, of whom nine had metastatic disease on pre-operative imaging. After maximal surgical resection, children received alternating blocks of myelosuppressive and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless local imaging (ie, from the child's treatment centre) showed progressive disease. FINDINGS: 50 of the 80 patients with non-metastatic disease progressed, 34 of whom were irradiated for progression. The 5-year cumulative incidence of freedom from radiotherapy for the 80 non-metastatic patients was 42% (95% CI 32-53). With a median follow-up of 6 years (range 1.5-11.3), overall survival for the non-metastatic patients at 3 years was 79.3% (95% CI 68.5-86.8) and at 5 years 63.4% (51.2-73.4). The corresponding values for event-free survival were 47.6% (36.2-58.1) and 41.8% (30.7-52.6). There was no significant difference in event-free or overall survival between complete and incomplete surgical resection, nor did survival differ according to histological grade, age at diagnosis, or site of disease. In 47 of 59 (80%) patients who progressed, relapse resulted from local control only. The median time to progression for the 59 patients who progressed was 1.6 years (range 0.1-10.2 years). The median age at irradiation of the whole group was 3.6 years (range 1.5-11.9). For the 80 non-metastatic patients, the 23 who achieved the highest relative dose intensity of chemotherapy had the highest post-chemotherapy 5-year overall survival of 76% (95% CI 46.6-91.2), compared with 52% (33.3-68.1) for the 32 patients who achieved the lowest relative dose intensity of chemotherapy. INTERPRETATION: This protocol avoided or delayed radiotherapy in a substantial proportion of children younger than 3 years without compromising survival. These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma.

A WT1 exon 1 mutation in a child diagnosed with Denys-Drash syndrome.

Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms tumor. DDS is associated with constitutional WT1 mutations, the majority being missense mutations in the zinc-finger region. A dominant-negative mode of action of the mutant DDS proteins is thought to explain the more severe genitourinary phenotype seen in DDS compared with children with complete deletion of one WT1 allele. We present a phenotypically female child who presented with bilateral Wilms tumor at 8 months of age. She was found to have an XY karyotype and diagnosed with DDS. In the constitutional DNA of this child we found a previously unreported mutation in exon 1 of WT1. This de novo mutation, delT in codon 40, is predicted to produce a termination signal in codon 90 (F40fsX90). This frameshift mutation results in a severely truncated protein, which would remove both the zinc-finger DNA-binding domain and the majority of the N-terminal regulatory domain, including regions previously shown in vitro to be necessary for inhibition of WT1 transcriptional activity. Our results provide important physiological evidence that the first 40 amino acids of WT1 are capable of functionally important interactions, presumably through their ability to self-associate with full-length WT1.