Other hypotheses currently being explored in I4C Gabriella Tikellis 6 th International I4C Meeting IARC 5-6 th October, 2013

Objectives of session  Raise awareness of other research questions currently being examined and for which data is available for pooling  Allow representatives from additional cohorts to consider how and when their data could contribute to the various research questions  Stimulate members to put forward ideas for new research proposals that could be examined through the I4C  Identify I4C members who are interested in being part of the various research areas

(1) The role of parity and birth order in the development of childhood cancers

o Led by Ora Paltiel (JPS) o Approval by Steering Committee at 2012 Lyon meeting o Utilize datasets currently being used for birth weight analysis

(2) The Prevalence of Postulated Risk Factors for Childhood Cancers among Cohorts from the International Childhood Cancer Cohort Consortium (I4C) Gabriella Tikellis, Martha Linet, Jean Golding, Camilla Stoltenberg, Sjurdur Olsen, Terence Dwyer

Aim To examine the ecologic association between the cohort prevalence of postulated risk factors for CL, with the cohort- specific incidence of CC/CL as a means of generating new hypotheses for future research.  Incidence based on cohort-data  Prevalence based on data currently available at IDCC  Increase in the number of factors to examine

Cohorts

Cancer-related  All childhood cancers  Leukemia  ALL  Age at diagnosis  Incidence rate based on person-years of follow up

Maternal  Age at time of baby’s birth (years)  Completed ≥12 years of education  Currently married/cohabitating  Smoked during pregnancy  Passive smoking at home  Alcohol consumption during pregnancy  Prenatal folic acid supplementation  Pre-pregnancy BMI, kg/m 2  Total pregnancy weight change, kg  Maternal height, cm  Diabetes (any)  Gestational diabetes  Prenatal x-ray: abdomen/pelvic area  Previous miscarriage  Exposure to pesticide during pregnancy  Caesarean delivery  Parity

Paternal  Age at time of baby’s birth (years)  Completed ≥12 years of education  History of diabetes

Index child  Birth type: Singleton /Twins / Triplets etc  Down’s Syndrome  Gender  Gestation age  Placental weight  Birth weight  Body length at birth  Head circumference at birth, cm  First born  Breastfed during first 6 months

(3) Parental (paternal) age and risk of childhood cancer

Background  Advancing paternal age is associated with an increased risk of childhood cancers among offspring.  The relationship between parental age has been examined in many studies but with inconsistent results which may be attributed to the small sample size of most of these studies and different reference groups used  Two large studies from Great Britain and Sweden have provide some support for an increased risk of some CC especially leukemia with older parental age. However, studies are not entirely consistent with respect to the impact of maternal versus paternal age.  Both maternal and paternal age have been linked to genetic aberrations in the offspring. Risk of germ cell sporadic mutations are more closely linked to paternal age, according to earlier assumptions as male germ cells undergo more cell divisions than female. In addition, paternal age is linked to leukocyte telomere length which in turn is linked to cancer risk.

Aims  Examine the association between paternal age and childhood cancers/ leukemia  Examine association between parents with large age differences (e.g. 5, 10 years)

Cohort data

Next steps  Datasets have been compiled for the 6 cohorts  Harmonize variables for pooling of datasets  Commence with data analysis plan

(4) Association between previous fetal loss and risk of childhood cancer in index child Proposal approved by I4C Steering Committee 15 May 2012 Current investigators: G Tikellis, W Ning, T Dwyer, J Golding, C Stoltenberg, S Olsen, O Paltiel, Tone Bjørge, M Linet, U M Reddy M Willinger

Aim Examine the association between a maternal history of any previous fetal loss and the risk of childhood cancers, particularly leukemia/ALL

Background  Retrospective case-control, record-linkage studies suggest an INCREASED risk associated with maternal history of any previous fetal loss and CC particularly ALL  Studies that have examined age at time of cancer diagnosis suggest a greater risk in cases diagnosed within first two years of life  Findings are unequivocal with magnitude of risk varying significantly between studies  Heterogeneity in findings may be due in part to differences in the classification of CC, the type of fetal loss examined, data sources used (record linkage, self administered questionnaires etc), small sample size

Fetal loss Maternal history of at least one previous:  Miscarriage(<20 weeks gestation)  Still birth (pregnancy loss ≥ 20 weeks gestation)  Abortion (induced)  Fetal loss immediately preceding the index pregnancy  Any previous fetal loss (combining any miscarriages, stillbirths, extra- uterine, +/- induced abortions)

Maternal  Parity  Demographics: age, education, marital status  Maternal smoking and alcohol consumption during pregnancy  Maternal obesity measures- pre-pregnancy BMI, pregnancy weight change  Maternal hormonal fertility treatment

Index child  Gestation age  Gender  Age at cancer diagnosis  Birth weight  Down’s Syndrome  Multiple birth

Currently available data * * Based on 10% of all live births

(5) Prenatal maternal infections and childhood cancers Prepared by Jessica Miller (Recipient of the Australian Endeavour Award)

Background - General maternal infections during pregnancy have been studied but findings have not been consistent or infection-specific o influenza/pneumonia were associated with a significantly increased risk of childhood leukaemia o increased risk of ALL in children if the mothers had recurrent infections, used antibiotics during pregnancy, or used antihistamines or allergy remedies before or during pregnancy o Studies on specific illnesses such as chicken pox, reactivated Epstein-Barr virus and herpes and their association with the onset of childhood cancer in the offspring have given inconclusive results. - Increasing evidence suggests an immune dysfunction at birth is present in children who subsequently develop ALL. Studies on neonatal blood spots of children who did and did not develop ALL found a lower lever of IL-10 - Childhood infections and the risk of childhood cancers using different proxies of infectious exposure in infancy but consistent results have not been observed. The proxies have ranged from socioeconomic status, residential location, parental social contacts outside of home, birth order, preschool attendance, breastfeeding, and infectious illness histories for child and mother

Aim To examine the association between prenatal maternal infections and the development of childhood cancers

Preliminary progress  Pooled questionnaire data from ALSPAC, MoBa, and DNBC - potential inclusion of JPS and CPP data  Women recruited between 1990 and 2007 – Total of 211,945 pregnant women followed (ALSPAC, MoBa, DNBC) – 281 cases of reported childhood cancers  When possible, trimester of reported infection and number of reported infection episodes will be examined

 Choice of prenatal maternal infections based on comparability of questionnaire data across cohorts – Self-reported symptoms of infections: vomiting, diarrhoea – Self-reported infections: genitourinary infection, genital herpes, vaginal thrush – Non-comparable illnesses include: common cold, influenza, throat and ear infection, fever & cough

Comparable prenatal maternal illnesses

Prenatal maternal illnesses

Future work - Need to clean and harmonize data from DNBC, CPP, JPS - Examine data collected from other cohorts at an earlier stage of follow up e.g. ELFE - Determine which infections can be pooled across the cohorts - Examine possibility of utlizing biospecimens to examine specific infections

New research ideas... Always welcome!  Initial discussions with a member of the Steering Committee  I4C IDCC can assist with identifying what data is available from which cohorts  Complete I4C Concept Proposal Form and submit to the I4C Steering Committee for approval

Concept Proposal Form: Appendix 2 of the I4C Policies and Procedures Manual