Research Program

The Childhood Cancer Research Group (CCRG) houses the National Registry of Childhood Tumours (NRCT), probably the most famous childhood cancer registry in the world. NRCT material is quite detailed and linkable to other datasets and often provides the platform for CCRG research activity. The CCRG undertakes national and international analyses of childhood cancer incidence, mortality and survival, as well as more complex research into the causes of cancer and outcomes of treatment. The CCRG has a newly emerging programme of laboratory-based research, and interview-based research with families affected by childhood cancer. Much of CCRG's research is conducted in collaboration with scientists elsewhere (e.g. members of the Children's Cancer and Leukaemia Group).

The main areas of research at the CCRG are described more fully below.

Incidence, mortality, survival and other outcomes and survivorship

The Department of Health, National Cancer Intelligence Network and Scottish Executive are largely responsible for funding these pieces of work, which provide childhood cancer intelligence and basic research linking to routinely available national datasets. International collaborations currently involve submissions of datasets to EUROCARE5 and ACCIS2, with EUROCARE covering survival, and ACCIS covering both incidence and survival in a population-based fashion. We also contribute to International Association of Cancer Registries research activities.

The NRCT's annual work programme, delivering national cancer intelligence, is agreed with the NCIN Children, Teenagers and Young Adults Site Specific Clinical Reference Group which oversees the work of the English Registries delivering childhood (CCRG) and teenage and young adult (North West Cancer Intelligence Services) cancer intelligence. Joint work between the two registries has been actively developed. Details of the two work programmes devised and agreed annually for the year April 2011 to March 2012 are available on the NCIN website. They are also regularly featured in the Children's Cancer and Leukaemia Group (CCLG) newsletter "CCLG Today" published every two months. The work programmes focus on topics that are clinically relevant and may help to improve outcomes.

Mortality data are less frequently reviewed, more usually in the context of specific cohort studies such as our retinoblastoma studies and the Sellafield and Dounreay investigation. Now it is possible to link Hospital Episode Statistics (HES) to NRCT data, particularly for registered cancers and hospital admission in England since 1997, we have begun studies of end of life care. We are also involved in monitoring the pattern of causes of death amongst childhood cancer patients to shed light on treatment-related toxicity, and to study late causes of death in long term survivors. One important feature of the 2011-12 NCIN work programme is to report on second primary tumours (SPT) amongst those diagnosed with childhood cancer who survive, in conjunction with NWCIS reporting the same data for TYA patients. Previous reports on SPTs following childhood cancer have been produced as part of our collaborative involvement in the British Childhood Cancer Survivor Study (BCCSS), which followed up all children with cancer registered on the NRCT to 1991, who survived five years or more subsequently. CCRG's attention is now concentrated on the groups not covered by BCCSS i.e. those who were diagnosed with childhood cancer at any time in the NRCT's history and developed a SPT within 5 years of diagnosis and separately on long term SPTs occurring in the children registered with cancer on the NRCT from 1992 onwards. There are now more than 20,000 adults living in the UK who had cancer in childhood, and whose needs should be addressed.

We are engaged in a major initiative to record directly all new childhood cancer registration information electronically, compatible with an effort to ensure all English cancer registrations take place in an entirely consistent format. The aim is to complete this transformation by April 2013. The speed with which we achieve completeness for a given registration year and the quality of data we acquire about stage of childhood cancer at diagnosis and treatment is expected to improve further by this means.

We are also funded by NCIN to investigate how meaningful is the concept of 'comorbidity' amongst childhood cancer patients (defined as non-cancer (therapy) related conditions, that may separately influence outcomes), the prevalence of such conditions as may contribute, and how such comorbidity and its effects might be routinely measured (e.g. in relation to excess hospital contact or quality of life).

NRCT record-based research[Top]

The NRCT provides an almost complete registration of children with cancer in Britain over many years (and for more recent years Northern Ireland also). Most of the children registered were also born in Britain, and for the overwhelming majority we are able to obtain their birth registration details, and to select matched birth registration details of control children unaffected by cancer. The information on cases and controls (linked to HES data for cases) provides a variety of information we can use e.g. birthweight, paternal occupation/social class, and area-census links providing characteristics of the residence at birth. International collaborations involve contributions to the Childhood Leukemia International Consortium and the Brain Tumor Epidemiology Consortium.

Our research activity, based on these records can be grouped in 4 main ways

The influence of gene structure on childhood cancer risk

The retinoblastoma (RB) gene makes the best described genetic contribution to childhood cancer risk. We have undertaken much research on retinoblastoma but currently are focusing on the long term consequences of possessing a heritable mutated form of the gene. We are studying the occurrence of subsequent primary tumours in children affected by the heritable form of retinoblastoma, and the interaction between the particular nature of the mutation present in the heritable form, treatment by irradiation/chemotherapy, and the development of subsequent primary tumours, particularly in the radiation field. We are also studying the very long term consequences of possessing a germline RB mutation, by assessing cancer risk and mortality in the parents of affected children who may themselves possess a germline mutation.

Further laboratory-based work may involve assessing the radiosensitivity of human cell-lines possessing particular RB mutations.

We are additionally collaborating with colleagues at the University of Newcastle in assessing the relationship between presence of a congenital malformation and risk of different cancers in the child. In conjunction with colleagues at the Institute of Cancer Research we collaborate in the Foetal Anomaly Childhood Tumour (FACT) study. Both these studies are predicated on the hypothesis of an overlap in the genetic basis of specific malformations and childhood cancer risk.

Intrauterine growth and childhood cancer risk

We have studied the reduced childhood cancer risk in twins and intend to take this further, including trying to define by what age, beyond childhood (age 0-14 years) the cancer risk becomes the same as that of the general population.

We have completed some initial studies, defining the birthweight risk relationship for leukaemia, and all other childhood cancers. We hope to define similar risk relationships for the period before birth year 1980, using the Oxford Survey of Childhood Cancers (OSCC) database, which would define birthweight (as a marker of intrauterine growth associated risk) as an enduring risk factor for childhood cancers.

We are pursuing some particular aspects of the relationship between birthweight and childhood cancer, as part of further studies defining why twins experience fewer childhood (and TYA) cancers than babies born as singletons, and in relation to conceptions following (treated) subfertility. In general babies so conceived have a slightly lower birthweight, and might therefore be at lower risk, but interest mainly centres on whether the medical procedures adopted for treatment, since the 1960s, tend to increase risk. Our intended laboratory-based studies into factors jointly determining birthweight and risk are also relevant.

Radiation (ionising and non-ionising) and childhood cancer risk

We include under the heading of our work on ionising radiation the updated investigations of cancer excesses observed at different times in the populations around the nuclear installations at Sellafield and Dounreay, even though any cancer risks observed may well not be due to ionising radiation exposure per se. More detail about this investigation can be found at the link Seascale and Dounreay.

Another major piece of work, whose first phase is nearing completion is the study of childhood cancer risk in relation to exposure to natural sources of ionising radiation (radon and gamma rays) across Britain. We have needed to assemble a large population of cases and controls, with their birth addresses across Britain, in order to have sufficient power to detect reliably the small relative risks that may be associated with exposure to such ionising radiation doses. Building on the results of the initial investigation we will proceed to a bigger second phase study, incorporating an even larger number of cases and controls, and considerably greater numbers of ionising radiation exposure measurements.

We are also investigating the effect of delivering ionising radiation as part of the treatment of initial primary childhood cancers. We are studying the occurrence of chemotherapy/radiotherapy related second primary tumours occurring in children with a primary retinoblastoma. The nature of the particular form of RB mutation in children with the heritable form of retinoblastoma may contribute to the risk of (radiation-induced) second primaries and we aim to investigate the influence of this radiosensitivity. We have also collaborated in the study of radiation-related risks for children with a wide variety of other primary childhood tumours, with the British Childhood Cancer Survivor Study (BCCSS) currently based in Birmingham, for children diagnosed with their first cancer by 1991, who subsequently survived five years. Further studies of second primary tumours in children who were diagnosed with their first tumour from 1992 onward, were treated and survived five years and went on to develop a second primary tumour or other health consequences, will almost certainly form part of future research, as will the apparent increase over time in the numbers of second primary tumours diagnosed early, i.e. within the first five years of survival.

There are few opportunities available to us to investigate risks associated with use of ionising radiation for diagnostic and imaging purposes (given that a national study of children and older teenagers exposed to computerised tomography, has already been underway at the University of Newcastle for several years). However it may be possible to resurrect a very large body of data from the Oxford Survey of Childhood Cancers (OSSCC) which may also contain detailed information on antenatal X-ray exposure of pregnant women, and study cancer risk in the child after birth. We will pursue this if possible.

Our work on non-ionising radiation exposure relates largely to further investigations of childhood cancer risk in relation to the electromagnetic fields (EMF) produced by the distribution of electricity to homes. We are analysing data for the period since that covered by the results of our original investigation (to 1995) in England and Wales, extending the analyses to cover Scotland, as well as England and Wales, and considering the fields which emanate from both underground and overhead cables transmitting at a wider range of voltages than we originally considered. We have completed studies of childhood cancer risk that might be associated with EMF exposure of the father through his occupation around the time of birth, but found little evidence of such occupationally associated risks.

Infection and childhood cancer risk

Part of our work in this area is based on the examination of ecological relationships between patterns of infectious disease population exposure and risk in the same population at subsequent (lagged) intervals. If the Oxford Survey of Childhood Cancers can be resurrected it may also be possible to use its considerable resources to study directly in a case-control fashion the documented/reported exposures of the families of cases and controls and cancer risks. Additionally we are developing laboratory-based approaches to making measurements of infection contact in tissue samples collected in case-control study designs.

Laboratory studies and field studies[Top]

We are engaged in a small range of laboratory studies, designed to develop approaches to measurements that can be made in tissue samples and integrated with epidemiological study designs. We have been mainly interested in developing approaches to assessing risk from contact with infection in utero, developing the technical approaches concerned with making measurements in neonatal dried blood spots (DBS) taken universally for neonatal screening purposes, and establishing which collections of neonatal DBS have been retained. We believe such collections do exist, though access may be restricted, and that it will be possible (whenever DBS samples have been freezer stored) to detect immunological evidence of infection contact during pregnancy. Detection of nucleic acid evidence of viral infections in pregnancy, if the viral nucleic acid persists in the blood, is also likely to be possible, even if the DBS have not been stored under stringent conditions.

We are separately interested to use the collection of DBS to study (epi) genetic factors controlling the intrauterine growth process, because of the strong evidence from our birthweight studies that such processes can be associated with increased risk of a variety of childhood tumours.

Apart from assembling case-control collections of tissue samples and obstetric data from hospital records, the only fresh collection of information in field studies involving family interviews/tissue sampling, is our intended involvement as one of 3 centres in the pilot phase of the International Study of non-CNS Embryonal Tumours (ISET) which is coordinated internationally by IARC, Lyon, and within the UK by the University of Manchester. We think this study will begin late in 2011.