Overview

Our research team has played a major role in the study concept and planning and is functioning as the I4C International Data Coordinating Centre. Data is being pooled and analysed to examine environmental and genetic factors that differ between those children who get cancer and those who don't.

How we started

The Director of the I4C International Coordinating Centre, Professor Terry Dwyer, was tasked in 2004 with leading an evaluation of whether the National Children's Study (NCS), a childhood cohort of 100,000 participants, would be sufficiently sized to include cancer as a workable outcome.

Given their rarity, these discussions concluded that the NCS alone would not have sufficient power to examine childhood cancers. However, it was agreed that collaborating with existing and planned large cohorts may provide the power to get prospective evidence on the potential causes of childhood cancers.

We held a workshop in 2005 in Rockville, MD, USA, to discuss the development of an international alliance of longitudinal studies of children. Research teams from 15 countries, spanning four continents and representing approximately 700,000 children, agreed to a collaboration leading to the establishment of the International Childhood Cancer Cohort Consortium (I4C).

Contact us

I4C
Murdoch Children's Research Institute
The Royal Children's Hospital
50 Flemington Road
Parkville VIC 3052
Australia

Gabriella Tikellis, Honorary Fellow
Email:  show email address

Our meetings

14th International Childhood Cancer Cohort Consortium (I4C) meeting

Professor Dwyer chaired the International Childhood Cancer Cohort Consortium (I4C) annual meeting in September 2023 at the International Agency for Research on Cancer (IARC) in Lyon, France.

Watch the 2023 I4C sessions on WHO

The meeting discussed how the restrictions introduced by the General Data Protection Regulation (GDPR) in Europe have restricted opportunities for sharing data collected in EU countries. While the consortium finds ways to overcome this problem, the testing of hypotheses on preventable causes of childhood cancer will slow.

Nonetheless, considerable progress has been made in the last year. The meeting heard that work on the association of maternal infection during pregnancy had shown considerable promise. Infections of the genitourinary (urinary) tract, in particular, were found to be associated in our pooled cohort data. While this does not confirm a causal association, it does suggest that future work in this area is worth prioritising

A study funded by the Frances and Augustus Newman Foundation in the UK to examine the presence of viral DNA in cord blood from infants in the Norwegian cohort (MOBA) of approximately 100,000 infants, is hoped to shine further light on this potentially important pathway.

Image: I4C Annual Meeting group of 2023

13th International Childhood Cancer Cohort Consortium (I4C) meeting

We held two live webinars on Wednesday 23rd and Thursday 24th February 2022. Sessions included:

• Recent findings from I4C – Maternal infection and risk of childhood leukemia - presented by Jianrong (Jeff) He.
• Mediation analysis in life-course studies – presented by Bianca de Stavola.
• Advances in measuring ETV6-RUNX1 translocations in cord blood – presented by Arndt Borkhardt.
• Recent findings from I4C – Maternal infection and risk of childhood leukemia - presented by Jianrong (Jeff) He.
• Recent findings in epigenetics on the aetiology of childhood leukemia – presented by Joseph Wiemels.
• Adv A strategy for investigating the causes of childhood cancer in China – presented by Yawei Zhang.

12th International Childhood Cancer Cohort Consortium (I4C) meeting 2020/2021

Held online in February 2021 due to the impact of COVID-19.

Research team

Principle Investigator
Professor Terry Dwyer

Project Manager
Ms Gabriella Tikellis

Lead Epidemiologist
Professor Anne-Louise Ponsonby
Email:  show email address

Data Management Coordinator
Mr Luke Stevens

Epigenetic Consultant
Professor Richard Saffery

Statistical Support

Statistical Advisor
Stan Lemeshow
Email: [email protected]

Senior Biostatistician
Gary Phillips
Email: [email protected]

Our research 

As of February 2019, the I4C International Data Coordinating Centre houses data on:

• 388,190 mothers and babies, including 719 cases of childhood cancer (215 leukaemia) from seven cohorts contributing data to the pooled analysis:
  • ALSPAC
  • CPP
  • DNBC (10% sample)
  • JPS
  • MoBa (10% sample)
  • NINFEA
  • TIHS

I4C Working groups

I4C Epigenetic working group

We have established working groups to examine epigenetic changes and various environmental exposures with childhood cancer. This working group is being headed by Dr Zdenko Herceg and Akram Ghantous (IARC, Lyon).

I4C Environmental Birth Weight working group

Led by Ora Paltiel from the Jerusalem Perinatal Study, this group investigated the association between childhood cancer, specifically leukaemia, with specific attention to maternal adiposity measures using prospectively collected pooled data from six birth/childhood cohorts in the I4C consortium.

There are two working groups examining pesticide exposure, both being led by Mary Ward, Leslie T. Stayner and Benjamin Booth, from NIH/NCI.

1. Parental Occupational Exposure
   The NCI led team are examining the association between parental occupations that involve exposure to pesticides (mainly farming) and the subsequent development of childhood cancer in their offspring. This will involve the development of an automatic conversion table from national classification systems for jobs to one international classification. The group aims to pool prospectively collected data from several I4C cohorts with detailed parental occupation and pesticide data.
2. Residential proximity and agricultural pesticide exposures
   This work aims to evaluate the risk of childhood cancers in relation to residence in, and distance from, agricultural areas during pregnancy and early life, while accounting for parental occupational exposure to pesticides. This will involve access to historical land cover maps for the I4C cohorts during the time of the cohort births and geocoding of residential addresses at the time of the index child's birth.

I4C Folate working group

Led by Professor Terry Dwyer, the group is examining the hypothesis that maternal prenatal folic acid supplementation is associated with a reduced risk of the index child developing childhood cancers, in particular, childhood leukaemia. The NIH has recently provided financial support to take this work forward.

The group will analyse data from four more established I4C cohorts that have data on folic acid: TIHS, ALSPAC, DNBC and MoBa. Newer cohorts such as the Japanese Environmental Children's Study (JECS) may soon contribute data to this work.

I4C Birth Order and Paternal Age working group

The association of birth order with the development of childhood cancer is being examined using the pooled dataset comprising six established birth cohorts (ALSPAC, CPP, DNBC, MoBa, TIHS). The hypothesis is that not being firstborn, or having higher parity is associated with a decreased risk of childhood cancer, particularly leukaemia. The work is being led by Ora Paltiel at the Hadassah Medical Center, Jerusalem.

Collaborators

Murdoch Children's Research Institute has been designated as the I4C International Data Coordinating Centre, highlighting the important international contributions the Institute is making to improve the health and wellbeing of all children.

Worldwide collaboration

The International Data Coordinating Centre is under the direction of Professor Terry Dwyer and includes Dr Gabriella Tikellis as Project Manager and Mr Luke Stevens as a Data Management Coordinator.

Importantly, the study has the backing of the USA's National Institutes of Health (NIH), which can be viewed as a sign of the scientific importance and promise of the study.

Around the world, several large infant/child prospective studies have been launched to examine environmental and biological determinants of common diseases. The rarity of virtually all forms of childhood cancer, however, prevents even large cohort studies from examining the relationship of common exposures with common types of childhood cancer because of inadequate sample size.

This project is spanning five continents with research teams from 15 countries.

Funding

The I4C wish to acknowledge the following funding partners:

• National Children's Study
• National Institutes of Health (NIH)
• National Cancer Institute (NCI)
• National Institute of Child Health and Human Development (NICHD)
• Children's Cancer Foundation
• International Agency for Research on Cancer (IARC)
• Rotary Club of North Brighton
• Tour de Cure
• Frances and Augustus Newman Foundation 
• Philanthropic donations within Murdoch Children's Research Institute

Publications

He J-R, Yu Y, Fang F, Gissler M, Magnus P, László KD, Ward MH, Paltiel O, Tikellis G, Maule MM, Qiu X, Du J, Valdimarsdóttir UA, Rahimi K, Wiemels JL, Linet MS, Hirst JE, Li J, Dwyer T. (2023). Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark. JAMA Netw Open, 6(2), e230133. 

He J-R, Hirst JE, Tikellis G, Phillips GS, Ramakrishnan R, Paltiel O, Ponsonby A-L, Klebanoff M, Olsen J, Murphy MFG, Håberg SE, Lemeshow S, F Olsen S, Qiu X, Magnus P, Golding J, Ward MH, Wiemels JL, Rahimi K, Linet MS, Dwyer T, International Childhood Cancer Cohort Consortium . (2022). Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts. Int J Epidemiol, 51(3), 769 - 777. DOI: 10.1093/ije/dyab199

He J-R, Hirst JE, Tikellis G, Phillips GS, Ramakrishnan R, Paltiel O, Ponsonby A-L, Klebanoff M, Olsen J, Murphy MFG, Håberg SE, Lemeshow S, F Olsen S, Qiu X, Magnus P, Golding J, Ward MH, Wiemels JL, Rahimi K, Linet MS, Dwyer T, International Childhood Cancer Cohort Consortium. (2022). Correction to: Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts. Int J Epidemiol, 51(3), 1037. 

Tikellis G, Dwyer T, Paltiel O, Phillips GS, Lemeshow S, Golding J, Northstone K, Boyd A, Olsen S, Ghantous A, Herceg Z, Ward MH, Håberg SE, Magnus P, Olsen J, Ström M, Mahabir S, Jones RR, Ponsonby AL, Clavel J, Charles MA, Trevathan E, Qian ZM, Maule MM, Qiu X, Hong YC, Brandalise S, Roman E, Wake M, He JR, Linet MS on behalf of the International Childhood Cancer Cohort Consortium. The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers. Paediatric and Perinatal Epidemiolology 2018 32(6):568-583.

Brown RC, Dwyer T, Kasten C, Krotoski D, Li Z, Linet MS, Olsen J, Scheidt P, Winn DM. Cohort profile: the International Childhood Cancer Cohort Consortium (I4C). International Journal of Epidemiology 36 (4) : 724 - 30(2007) PubMed.

Patel DM, Gyldenkærne S, Jones RR, Olsen SF, Tikellis G, Granström C, Dwyer T, Stayner LT, Ward MH. Residential proximity to agriculture and risk of childhood leukemia and central nervous system tumors in the Danish national birth cohort. Environ Int. 2020 Oct;143:105955. doi:10.1016/j.envint.2020.105955. Epub 2020 Jul 22.

Lewis P, Hellmich M, Fritschi L, Tikellis G, Morfeld P, Groß JV, Foster RG, Paltiel O, Klebanoff MA, Golding J, Olsen S, Magnus P, Ponsonby AL, Linet MS, Ward MH, Caporaso N, Dwyer T, Erren TC. Perinatal photoperiod and childhood cancer: pooled results from 182,856 individuals in the international childhood cancer cohort consortium (I4C). Chronobiol Int. 2020 Jul;37(7):1034-1047. doi: 10.1080/07420528.2020.1740724. Epub 2020 Apr.

He JR, Ramakrishnan R, Hirst JE, Bonaventure A, Francis SS, Paltiel O, Håberg SE, Lemeshow S, Olsen S, Tikellis G, Magnus P, Murphy MFG, Wiemels JL, Linet MS, Dwyer T. Maternal Infection in Pregnancy and Childhood Leukemia: A Systematic Review and Meta-analysis.   J Pediatr. 2020 Feb;217:98-109.e8. doi: 10.1016/j.jpeds.2019.10.046. Epub 2019 Dec 4.           

Patel DM, Jones RR, Booth BJ, Olsson AC, Kromhout H, Straif K, Vermeulen R, Tikellis G, Paltiel O, Golding J, Northstone K, Stoltenberg C, Håberg SE, Schüz J, Friesen MC, Ponsonby AL, Lemeshow S, Linet MS, Magnus P, Olsen J, Olsen SF, Dwyer T, Stayner LT, Ward MH; International Childhood Cancer Cohort Consortium. Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C). Int J Cancer. 2020 Feb 15;146(4):943-952. doi: 10.1002/ijc.32388. Epub 2019 May 24.

Paltiel O, Lemeshow S, Phillips GS, Tikellis G, Linet MS, Ponsonby AL, Magnus P, Håberg SE, Olsen SF, Granström C, Klebanoff M, Golding J, Herceg Z, Ghantous A, Hirst JE, Borkhardt A, Ward MH, Holst Søegaard S, Dwyer T. The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C). International Journal of Cancer. 2019;144(1):26-33. doi: 10.1002/ijc.31635. Epub 2018 Oct 26.

Tikellis G, Dwyer T, Paltiel O, Phillips GS, Lemeshow S, Golding J, Northstone K, Boyd A, Olsen S, Ghantous A, Herceg Z, Ward MH, Håberg SE, Magnus P, Olsen J, Ström M, Mahabir S, Jones RR, Ponsonby AL, Clavel J, Charles MA, Trevathan E, Qian ZM, Maule MM, Qiu X, Hong YC, Brandalise S, Roman E, Wake M, He JR, Linet MS; The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers. Paediatr Perinat Epidemiol. 2018 Nov;32(6):568-583. doi: 10.1111/ppe.12519. Epub 2018 Nov 22.

Paltiel O, Tikellis G, Linet M, Golding J, Lemeshow S, Phillips G, Lamb K, Stoltenberg C, Håberg SE, Strøm M, Granstrøm C, Northstone K, Klebanoff M, Ponsonby AL, Milne E, Pedersen M, Kogevinas M, Ha E, Dwyer T; International Childhood Cancer Cohort Consortium. Birthweight and Childhood Cancer: Preliminary Findings from the International Childhood Cancer Cohort Consortium (I4C). Paediatr Perinat Epidemiol. 2015 Jul;29(4):335-45. doi: 10.1111/ppe.12193.

Ghantous, A., Hernandez-Vargas, H., Byrnes, G., Dwyer, T., & Herceg, Z. (2015). Characterising the epigenome as a key component of the fetal exposome in evaluating in utero exposures and childhood cancer risk. Mutagenesis, 30(6), 733-742. doi:10.1093/mutage/gev010

Dwyer T, Tikellis G, Ghantous A, Lemeshow S, Haberg SE, Olsen J, Paltiel O, Golding G, Linet MS, Herceg Z, Munthe-Kaas MC, Stoltenberg C. MoBa and the International Childhood Cancer Cohort Consortium (I4C).  Norsk Epidemiologi 2014; 24 (1-2): 129-133

Ghantous A, Saffery R, Cros MP, Ponsonby AL, Hirschfeld S, Kasten C, Dwyer T, Herceg Z, Hernandez-Vargas H. Optimized DNA extraction from neonatal dried blood spots: application in methylome profiling. BMC Biotechnol. 2014 Jul 1;14:60. doi: 10.1186/1472-6750-14-60.