childhood and young adult cancer in the jerusalem perinatal study (jps) ora paltiel school of public...
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Childhood and Young Adult Cancer in
The Jerusalem Perinatal Study(JPS)
Ora Paltiel
School of Public Health and Dept of Hematology, Hadassah-Hebrew
University, Jerusalem Israel
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JPS
• Research cohort established in 1964-76
• All births to residents of West Jerusalem (92,408 children; 42,956 mothers; 39,620
fathers)
• Active surveillance of infant mortality, birth defects and pregnancy complications
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Harlap et al Paed Perinatal Epidemiology 2007; 21:256-73.
J e r u s a l e m P e r i n a t a l S t u d y
Age 17
Follow up cancer and mortality
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Mass immigration to Israel
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*Preconception
Pregnancycomplications
and outcomes
Life events after delivery
cancer
mortality
time
To what extent do events during early
human development or peripartum affect
cancer incidence and mortality over a
lifetime in the Israeli population?
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JPS cancer types age <15
Leukemias; 41
Lymphomas; 39
Nervous system; 37
Neuroblastoma; 10
Retinoblastoma; 7
Nephroblastoma; 5
Carci-noma;
4
Rhab-domyosarco ma, 2
bone; 18
other; 9
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Birth Weight and Cancer
• Low birth weight traditionally considered risk factor for future health outcomes
• Recent concern regarding effects of high birth weight
• Relation between high birth weight and cancer in children and adults
• Most consistent relationship: high birth weight and acute leukemia
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Proposed mechanisms:• Growth factors – eg IGF-1 related both to birthweight and
carcinogenesis
• Hormone levels eg estriol – related to fetal growth and breast cancer
• Genomic imprinting – syndromes related to both macrosomia and tumors
• Genetic susceptibility- genes related to birth weight and cell proliferation
• N - Larger population of preneoplastic clones
• Exposures eg pelvic radiation in mothers with large babies
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In 2000: 88,829 (97.1%) offspring from the JPS were traced and linked to the Israel Cancer Registry
Methods:
Objective:
To evaluate the association between birth weight
and leukemias in the JPS
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004
High Birth Weight and Cancer
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Distribution of birth weights JPSall newborns vs children with cancer
birth weight (kg)
Fre
qu
en
cy
20000
15000
10000
5000
0
Std. Dev = .54
Mean = 3.25
N = 86647.00
birth weight (kg)F
req
ue
ncy
80
60
40
20
0
Std. Dev = .50
Mean = 3.32
N = 499.00
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1.00
2.21
3.09
3.96
0
1
2
3
4
5
<3000 3000-3499 3500-3999 ≥4000birth weight (gram)
RR
RR for all leukemia n=65 by birth weight
RR for ALL n=41 RR for AML n=21
P for linear trend = 0.002
1
4.193.76
4.63
0
1
2
3
4
5
<3000 3000-3499 3500-3999 ≥4000birth weight (gram)
RR *
**
*P <0.05
1 0.72
2.593.46
0
1
2
3
4
5
<3000 3000-3499 3500-3999 ≥4000birth weight (gram)
RR
*
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004
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Birth weight and its relation to other cancers
• All sites (860) …………………. 2.05 (1.36-3.10) • Lymphoma (170) ………………1.50 (0.90-2.50)• Sarcoma (47) …………………..2.08 (0.87-4.90)• Breast cancer (96) ……………. 0.45 (0.14-1.43) • Melanoma (65) …………………2.32 (1.13-4.78) • Thyroid (96) …………………….0.52 (0.17-1.67)• Testicular (50) ………………….2.29 (1.02-2.75)
*Adjusted for maternal age at birth, gender (where relevant), socioeconomic status, ethnic origin of mother and family history
RR* for birthweight >4000gm (compared to 2500-3999 gm)
Cancer site (N)
Paltiel O, Deutsch L, in prep
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Having high BW sibling and leukemia
• For any sibling weighing >3500 gm• All leukemias: HR 1.94(1.2-3.1)• For ALL: HR 1.48 (0.8-2.8)• For AML: HR 3.1(1.4-7.1)
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Relative risk of leukemia of mothers by offspring birthweight
0
0.5
1
1.5
2
2.5
3
3.5
4
>1500 1500-4499
<4500
Rel
ativ
e R
isk
Birthweight (gr)
*
Ref.
Paltiel O et al Leukemia Res. 2008
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Cancer in children with congenital malformations
Preliminary results from the JPS
Paltiel, O, Yanetz R in prep
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Carcinogenesis and teratogenesis may be related
The cause of most birth defects is unknown
Furthermore, risk factors for cancer in children and young adults are largely undiscovered
Genes and developmental processes involved in fetal development may also be important in neoplasia
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Background-evidence
• Down syndrome: increased risk of leukemia
• Other genetic diseases – Beckwith Wiedemann, Goldenhar, Sturge-Weber etc increased risk of specific neoplasms
• Previous studies have been case reports, case series and occasionally case control studies
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Demographic characteristics of children born with and without malformations
With Without
Male 64% 51%
Birthweight <2500 gm 10% 7%
Mother smoker 28% 23%
Mother’s age at birth >35 13% 12%
Father’s age at birth >35 27% 27%
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Cancer in children with and without malformations
Relative Risk (95% CI)1.35) 1.06-1.71 (p=0.01
0
0.5
1
1.5
2
Severity of malformation
Rel
ativ
e R
isk
mild/moderate severe
)0.88-1.72(
)1.18-2.27(
P=0.03
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Severity of malformations and risk of cancer(compared to those without malformations)
0
1
2
3
4
solid tumors breast sarcoma testis
Rel
ativ
e R
isk
mild moderate severe
)0.99-2.11(
)0.38-6.4(
)0.32-5.28(
)2.96-6.74(
)0.29-5.02(
)1.21-9.39(
)0.98-5.36(
)0.38-6.4(
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Are congenital anomalies related to cancer in siblings or parents
• No association in siblings• Association between cleft lip/palate with
genitourinary cancer in parents (esp. mothers)
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The Risk of Cancer following Hospitalization for Infection in Infancy
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.
Objective: to evaluate the relation between hospital admission
in the 1st year of life due to infectious disease and the risk of
developing malignancy in childhood and early adulthood.
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Controversial relation between infections in infancy and subsequent cancer risk in
children and young adults
Childhood ALL, Hodgkin’s lymphoma
Protective effect of early infectious exposures
Non–Hodgkin’s lymphoma
1. Possibly induced by infectious stimulation
2. Immune defects and immunosuppression known risk factors.
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Methods:
27,401 offspring: Complete information on hospital admissions in the 1st year of life
Exposed - at least one hospital admission due to infectious disease in the 1st year of life.
Nonexposed - no hospitalization for infection in the 1st year of life
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.
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2,016 (8%) were admitted at least once for infectious causes in the 1st year of life.
Hospitalization for infection related to:
Lower birth weight
Higher birth order
Lower socioeconomic status
Less educated mothers
Results:
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.
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HospitalizedNot
Hospitalized
n n RR P
Any malignancy 21 262 0.88 0.59
Leukemia 1 25 0.44 0.45
Non–Hodgkin’s lymphoma
6 19 3.46 0.019
We found a 3-fold increased risk of non–Hodgkin’s lymphoma after 1st year hospitalizations due to infectious diseases.
Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.
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Children with a minor immunologic defects
Speculated mechanism:
Infection↑ Non-Hodgkin Lymphoma
High mortality in the past
Higher survival at present
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Could this be one of the causes of the increase in NHL incidence observed worldwide?
Age-adjusted Incidence of non-Hodgkin Lymphoma (NHL) US
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Familial cancer in the JPS
• Most cancers are sporadic
• Rare opportunity (outside Scandinavian family cancer registries) to study familial cancers in a population-based study
• Heritable germline mutations are common in the Israeli population
– BRCA 1 breast, ovarian – BRCA 2 breast, prostate – APC Colon
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Maternal region of origin-JPS
33%
29%
23%
15%
Israel Asia Africa West
35%
31%
20%
14%
47% 25%
18%
10%
Offspring with cancer (N=1093)
Mother-Offspring Pairs (N=176)
All Offspring (N=91,459)
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Distribution (%) of cancer sites for mothers with and without affected
offspring
22.6
42
9
19
47
9
0%
20%
40%
60%
80%
100%
Mothers withoutaffected offspring
Mothers with affectedoffspring
NHL
Ovary
Cervix
Thyroid
Uterus
Melanoma
Colorectal
Breast
Other
Paltiel et al Fam. Cancer 2007;6:121-129
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Distribution of cancer sites for offspring with and without affected mothers
35.8
12.2
8.9
8.7
8.4
7.5
26.6
4.8
10.5
12.4
13.3
10.5
0%
20%
40%
60%
80%
100%
Offspring without affectedmothers
Offspring with affectedmothers
Medulloblastoma
Sarcoma
MelanomaTestis
NHL
Thyroid
Leukemia
BreastHodgkin Disease
Other
Paltiel et al Fam. Cancer 2007;6:121-129
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Cancers among sib-ships
N=16 families
• 25% of mothers also had malignancy• In 50% of families sites were concordant :
Lymphoma (N=3)
Breast (N=2)
Ovary (N=1)
Testis (N=1)
Melanoma (N=1)
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Cancers among sib-ships
N=16 families
• 25% of mothers also had malignancy• In 50% of families sites were concordant :
Lymphoma (N=3)
Breast (N=2)
Ovary (N=1)
Testis (N=1)
Melanoma (N=1)
Family #1
3 siblings diagnosed within 4 years (1970-1974)
Family #2
2 siblings diagnosed within 3 years (1965-1968)
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DISTRIBUTION OF THE TIME INTERVAL BETWEEN DIAGNOSIS OF MOTHER-CHILD PAIRS: OBSERVED & EXPECTED BY CHANCE
0
10
20
30
40
1.50 4.50 7.50 10.5 13.5 16.5 19.5 22.5 25.5 28.5 31.5years
freq
uen
cy
observed expected
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Absolute interval (yrs) between diagnosis of mother and offspring
Paltiel et al Fam. Cancer 2007;6:121-129
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Familial Cancer JPS: Next steps
• Updated linkage with cancer registry• Detailed analysis of updated offspring-mother,
offspring-father and sibling pairs• Mother-Father pairs: clues to environmental
etiologies• Eventually…..detailed epidemiologic study
including genetic, epigenetic and extensive exposure analysis
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Preconception
Pregnancycomplications
and outcomes
Life events after delivery
cancer
time
Summary:
Exposures during the pre,peri- and postnatal period, have an impact on parents’ and offspring’s cancer risk.
• Unique population• Unique opportunities• Unique findings, requiring
confirmation in other populations• Potential for collaborations
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Acknowledgments• JPS staff 1964-2007: Investigators, nurses and
field workers and statisticians• Current team:
Investigators: R. Calderon-Margalit, Y. Friedlander, O. Manor,V. Meiner, O.Paltiel
• PhD candidates: M Avgil, H Hochner, E. Tiram, Y Wolff
• Statisticians and Programmers: L. Deutsch, N. Sharon, R. Yanetz
• Research collaborators for Israel: U. Elchalal, D. Hochner, R. Pollock A. Samuelov, D. Varon, E . Hayam
• Columbia University, New York K.R. Kleinhaus, M.C.Perrin, A.I.Neugut, M.B.Terry, S.Harlap
• New York University D.Malaspina
• Yale University E.Funai• U. of Washington D. Siscovick,
M. Williams• Funding: NIH; NARSAD
• Ministry of Interior• Ministry of Health- Cancer Registry• Ministry of Justice• Central Bureau of Statistics• Hadassah: Legal Bureau and IRB• Hebrew University Cosell Center
AND ALL PARTICIPANTS IN JPS STUDIES