Molecular cancer survivorship: paediatric brain tumour survivors
Research type
Research Study
Full title
Molecular cancer survivorship: Understanding host factors associated with neurocognitive late-effects in childhood brain tumour survivors
IRAS ID
308058
Contact name
Rebecca Hill
Contact email
Sponsor organisation
The Newcastle Upon Tyne NHS Foundation Trust
Duration of Study in the UK
1 years, 1 months, 30 days
Research summary
Whilst the survival outcomes in childhood cancer continue to improve, survivors often have tumour and/or treatment related late-effects. Greater than 50% of childhood cancer survivors have at least one chronic medical problem in the two years following diagnosis. In the same timeframe, at least 25% of survivors will have a severe chronic health condition. Neurological and neuro-cognitive late-effects are particularly devastating and more frequently observed in childhood cancer survivors of brain tumours largely due to the use of cranial radiotherapy leading to radiotherapeutic brain injury.
Childhood cancer survivors of medulloblastoma, the most common malignant brain tumour of childhood, frequently display decreasing cognitive performances over time and, for example, are less likely to achieve a higher degree when compared to their siblings. Despite these devastating consequences, the underlying biological mechanism associated with radiotherapeutic brain injury and poor neuro-cognitive outcomes are not understood. There is, however, emerging evidence that host genetic factors exacerbate radiotherapeutic brain injury, possibly explaining why the severity of neuro-cognitive late-effects differs greatly between childhood cancer survivors with comparable diagnoses and treatment regimens.
Researchers within the Paediatric Brain Tumour Group (PBTG), Newcastle University Centre for Cancer (NUCC), have designed a MassARRAY iPLEX assay for the targeted genotyping of 38 single nucleotide polymorphisms (SNPs), selected due to their reported association with neuro-cognitive outcomes in large genetic studies of childhood cancer survivors. Initial pilot data analysing these 38 SNPs within the PBTG medulloblastoma clinical trials cohorts have identified specific relationships between certain host SNP genotypes and neuro-cognitive outcomes in medulloblastoma survivors. These SNPs are typically involved in processes such as metabolism, DNA maintenance and repair, neural growth and repair, oxidative stress and inflammation.
This prospective pilot study will interrogate host SNPs in a patient cohort of brain tumour survivors at the Great North Children’s Hospital (GNCH). We will address the increasingly urgent need to identify and understand factors associated with survivorship, providing the foundation to develop new approaches to mitigate these factors and improve quality of survival in brain tumour patients.
Lay summary of study results: The purpose of this study was to assess whether it is possible to set up and conduct a clinical study to examine the associations between patient host genetic factors and neurocognitive outcomes after childhood brain tumour treatment. This was a prospective study, implemented in the neuro-oncology clinic at the Great North Children’s Hospital.
Patients were recruited from the neuro-oncology clinic. Participants were required to provide a single blood sample, planned at a time they were having a blood test or intravenous cannula for their routine follow-up. Participants and their families also completed a questionnaire collecting socio-economic status (SES) data. This questionnaire was a new tool designed specifically to assess the SES of participants in the UK and piloted within this study.
Clinical data was collected from the medical records. The results of neurocognitive assessments performed as part of routine assessment were collated for each patient. DNA was extracted from each of the blood samples. This DNA was used to sequence 40 specific genetic changes, known as single nucleotide polymorphisms (SNPs), using a method called amplicon sequencing. Statistical tests, called univariate and multivariate linear regression analysis, were then used to examine the relationships between the SNPs and neurocognitive outcomes in participants.
The study was set up, granted HRA/REC approval and implemented in the neuro-oncology clinic within 12 months. Between November 2022 and June 2023, 44 patients were enrolled in the study. This is 100% of patients who were offered enrolment. Patient recruitment was faster than expected. All of the clinical data were collected from the medical record and all participants had at least one completed neurocognitive assessment. All participants completed and returned the SES questionnaire, the majority completed all the questions. DNA was extracted from 100% of the blood samples. The SNPs of interest were successfully sequenced in all patient samples.
Full-scale intelligence quotient (FSIQ) was used to assess neurocognitive ability. The average FSIQ in brain tumour survivors was 20 points lower that the average FSIQ in the general population. The younger age at diagnosis is associated with a reduction in FSIQ following treatment. Having a change, also known as the reference allele, in the SNP rs1050450 is associated with having a lower FSIQ following treatment.
The successful set-up of this study has established a platform for the examination of the of the molecular, clinical and social determinants of neurocognitive late effects. Childhood brain tumour survivors are motivated to engage with molecular survivorship research, even with components that are invasive (blood sampling) or intrusive (sensitive SES information) in nature. Associations between clinical and genetic factors and neurocognitive outcomes in brain tumour survivors were identified.
This study now requires expansion to recruit a larger patient cohort for more rigorous examination of the development of neurocognitive late effects. The success of this pilot study provides a study design that can be expanded into multiple centres across the UK and funding has been secured for this multicentre expansion.REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
22/EM/0178
Date of REC Opinion
12 Aug 2022
REC opinion
Further Information Favourable Opinion