Other hypotheses currently being explored in I4C

Gabriella Tikellis6th International I4C Meeting

IARC 5-6th 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 I4C-member Cohorts Recruitment Study size Recruitment Childhood Cancer

(Included in this study) Years (Live births) Status Ascertainment Avon Longitudinal Study of Parents and Children /Children of the 90s 1990-1992 14,062 Completed 1992 Completed to 15 years (ALSPAC) - UNITED KINGDOM Collaborative Perinatal Project (CPP) 1959-1966 58,000 Completed 1966 Completed to ~8 years -USA

Danish National Birth Cohort (DNBC) 1996-2002 96,986 Completed 2002 Ongoing-completed to 8yrs -DENMARK Jerusalem Perinatal Study (JPS) 1964-1976 90,079 Completed 1976 Completed to 15 years - ISRAEL Norwegian Mother and Child Cohort Study (MoBa) 1999-2007 108,487 Completed 2008 Ongoing-completed to 8yrs - NORWAY Tasmanian Infant Health Survey (TIHS) 1988-1995 10,628 Completed 1995 Completed to 15 years - AUSTRALIA

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 educationCurrently married/cohabitating

Smoked during pregnancyPassive smoking at homeAlcohol consumption during pregnancy

Prenatal folic acid supplementation

Pre-pregnancy BMI, kg/m2

Total pregnancy weight change, kgMaternal 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 usedTwo 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

ALSPAC CPP DNBC JPS MoBa TIHSRECRUITMENT YEARS 1991-1992 1959-1966 1996-2002 1964-1976 1999-2007 1987 to 1995 LIVE BIRTHS, WITH DATA ON PAT AGE 11,720 39,224 8,667 86,211 11,158 10,393 167,373All cancers 20 50 145 163 106 27 511 - Leukemia 4 16 62 39 41 4 166 - ALL 2 11 54 26 33 2 128

Paternal age, years 30.72 ± 5.74 28.26 ± 6.97 32.80 ± 5.15 31.60 ± 6.85 32.79 ± 5.35 27.10 ± 5.88Maternal age, years 28.00 ± 4.96 24.14 ± 5.94 30.51 ± 4.24 27.66 ± 5.66 30.26 ± 4.58 24.33 ± 4.86

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

*Cohort Live births with previous

pregnancies

Number of cancer cases

Number of leukemia

cases

Number of ALL

Previous miscarriage

32%2,808

CPP 25%(Collaborative Perinatal Project)

Miscarry/abort 9,489

32%1,612

JPS 32,582 66 18 13 31%10,165

30%2,086

Total 78,971 259 91 68 33% (26,160)

ALSPAC 8,870 13 4 2

37,519 37 10 6

DNBC 5,070* 82 33 28

MoBa 6,973* 61 26 19

* 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-specifico 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

ALSPAC DNBC MoBa

TIHS CPP JPS

Inflammation/Infection No Yes No

No ? ?

Throat infection No No Yes

No ? ?

Ear infection No No Yes

No ? ?

Fever No Yes Yes

No ? ?

Cough No Yes Yes

No ? ?

Influenza Yes No Yes

No ? ?

Diarrhoea Yes Yes Yes

No ? ?

Vomiting Yes Yes Yes

No ? ?

Genital Herpes Yes Yes Yes

No ? ?

Prenatal maternal illnesses

ALSPAC MoBA

Childhood cancer Childhood cancer

No Yes No Yes

Maternal illness N (%) N (%) N (%) N (%)

Vomiting 6674 (47.6) 14 (58.3) 4035 (36.3) 38 (35.8)

Diarrhoea 5528 (39.4) 9 (37.5) 2259 (20.3) 22 (20.8)

Genitourinary infection 1667 (11.9) 2 (8.3) 1089 (9.8) 12 (11.3)

Genital herpes 72 (0.5) 0 (0.0) 82 (0.7) 1 (0.9)

Vaginal thrush 2917 (20.8) 3 (12.5) 2847 (25.6) 29 (27.4)

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

https://communities.nci.nih.gov/i4c/default.aspx