Genetic epidemiology of childhood cancer

Research on the genetic epidemiology of childhood cancer is led by Dr Pam Thompson and Professor Jill Birch.  The Manchester Children’s Tumour Registry (MCTR), was established by Professor Birch as a resource for aetiological studies of childhood cancer. The MCTR has lead studies investigating the incidence and patterns of cancer and congenital anomalies in the families of children with cancer, including ground-breaking work on Li-Fraumeni Syndrome.

Cancer is the most common natural cause of death in persons aged 13-24 years and yet little is known about aetiology of teenage and young adult (TYA) cancer. The group has published a series of seminal papers presenting results of analyses of national cancer data on TYAs which has contributed significantly to the award of the first ever Chair in Adolescent Oncology, funded by the Teenage Cancer Trust, to Manchester.

The Centre (through Dr Thompson) is part of the Childhood Leukaemia International Consortium (CLIC) which was initiated by a group at the University of California, Berkeley. Participants include groups from USA, France, Australia, Canada and the UK, and part of a collaborative project with the Manchester Centre for Genomic Medicine and Dr Celia May at the University of Leicester, using next generation sequencing data to identify rare/low frequency genetic variants that predispose to childhood leukaemia.

The Centre is also involved (through Dr Thompson) in a new international consortium to investigate childhood brain tumour epidemiology (the Brain Tumour Epidemiology Consortium (BTEC)), which promises to be the world’s largest consortium of researchers focused on identifying new risk factors for childhood brain tumours, including more than 8,000 affected children and 31,000 controls from 13 different epidemiological studies, representing 9 institutions from 7 countries around the world, to identify novel risk factors for these rare tumours. The goals of the consortium are to advance understanding of the aetiology of childhood brain tumours by contributing vital new information about the molecular, genetic, and environmental factors that may increase risk.  Discovery of novel risk factors has the potential to lead to substantial improvements in prevention and outcomes of childhood brain tumours.

Previous work on fine-scale haplotype analysis of genome-wide association study (GWAS) data from the region of the Major Histocompatibility Complex (MHC) on chromosome 6 most strongly associated with childhood acute lymphoblastic leukaemia showed very interesting differences in underlying rates of meiotic recombination, visible at the population level, between groups with leukaemia and controls, which may be underpinned by genotype at the PRDM9 locus. This has lead to an ongoing collaboration with Dr Celia May, who is an expert on homologous recombination and the role of PRDM9 in this process and Dr David Gilham at the Institute of Cancer Sciences. This project is an investigation of the meiotic regulator, PRDM9, as a potential contributor to childhood leukaemia development.

This project stemmed from the results of our bioinformatics analyses and aims to:

  • determine the germline frequency of rare alleles of PRDM9 in children B-cell precursor and T-cell acute lymphoblastic leukaemia
  • determine whether PRDM9 is expressed in leukaemic blasts
  • compare expression of different PRDM9 alleles

Current research projects

  • Identification of novel pathogenic inherited variants predisposing to childhood rhabdomyosarcoma
  • Expression of the meiotic regulator, PRDM9, by childhood leukaemia
  • International genome wide association study of hepatoblastoma
  • Molecular and genomic epidemiology of Wilms tumour
  • Cohort study of p53 related early onset breast cancer (COPE)