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Childhood and Young Adult Cancer in The Jerusalem Perinatal Study (JPS)

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. JPS. Research cohort established in 1964-76

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Childhood and Young Adult Cancer in The Jerusalem Perinatal Study (JPS)

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  1. 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

  2. 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

  3. 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 Harlap et al Paed Perinatal Epidemiology 2007; 21:256-73.

  4. Mass immigration to Israel Harlap

  5. To what extent do events during early human development or peripartum affect cancer incidence and mortality over a lifetime in the Israeli population? Pregnancy complications and outcomes *Preconception Life events after delivery cancer mortality time

  6. JPS cancer types age <15

  7. 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 cancerin children and adults • Most consistent relationship: high birth weight and acute leukemia

  8. Proposed mechanisms: • Growth factors – eg IGF-1 related both to birthweight and carcinogenesis • Hormone levelsegestriol – 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 • Exposuresegpelvic radiation in mothers with large babies

  9. High Birth Weight and Cancer Objective: To evaluate the association between birth weight and leukemias in the JPS Methods: In 2000: 88,829 (97.1%) offspring from the JPS were traced and linked to the Israel Cancer Registry Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004

  10. Distribution of birth weights JPSall newborns vs children with cancer

  11. * * * * RR for all leukemia n=65 by birth weight P for linear trend = 0.002 RR for ALL n=41 RR for AML n=21 Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004 * P <0.05

  12. Birth weight and its relation to other cancers Cancer site (N) RR* for birthweight >4000gm (compared to 2500-3999 gm) • 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 Paltiel O, Deutsch L, in prep

  13. 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)

  14. Relative risk of leukemia of mothers by offspring birthweight * Relative Risk Ref. <1500 1500-4499 >4500 Birthweight (gr) Paltiel O et al Leukemia Res. 2008

  15. Cancer in children with congenital malformations Preliminary results from the JPS Paltiel, O, Yanetz R in prep

  16. 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

  17. 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

  18. Demographic characteristics of children born with and without malformations

  19. Cancer in children with and without malformations Relative Risk (95% CI) 1.35 (1.06-1.71) p=0.01 (1.18-2.27) (0.88-1.72) P=0.03

  20. (1.21-9.39) (2.96-6.74) (0.98-5.36) (0.38-6.4) (0.38-6.4) (0.99-2.11) (0.32-5.28) (0.29-5.02) Severity of malformations and risk of cancer(compared to those without malformations)

  21. 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)

  22. The Risk of Cancer following Hospitalization for Infection in Infancy 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. Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

  23. 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 • Possibly induced by infectious stimulation • 2. Immune defects and immunosuppression known risk factors.

  24. 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.

  25. Results: 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 Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

  26. 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.

  27. Non-Hodgkin Lymphoma Infection ↑ High mortality in the past Higher survival at present Speculated mechanism: Children with a minor immunologic defects

  28. Could this be one of the causes of the increase in NHL incidence observed worldwide? Age-adjusted Incidence of non-Hodgkin Lymphoma (NHL) US

  29. 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

  30. Maternal region of origin-JPS Offspring with cancer (N=1093) All Offspring (N=91,459) Mother-Offspring Pairs (N=176)

  31. Distribution (%) of cancer sites for mothers with and without affected offspring Paltiel et al Fam. Cancer 2007;6:121-129

  32. Distribution of cancer sites for offspring with and without affected mothers Paltiel et al Fam. Cancer 2007;6:121-129

  33. 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)

  34. 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)

  35. DISTRIBUTION OF THE TIME INTERVAL BETWEEN DIAGNOSIS OF MOTHER-CHILD PAIRS: OBSERVED & EXPECTED BY CHANCE

  36. Absolute interval (yrs) between diagnosis of mother and offspring Paltiel et al Fam. Cancer 2007;6:121-129

  37. 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

  38. Unique population • Unique opportunities • Unique findings, requiring confirmation in other populations • Potential for collaborations Summary: Pregnancy complications and outcomes Preconception Life events after delivery cancer time • Exposures during the pre,peri- and postnatal period, have an impact on parents’ and offspring’s cancer risk.

  39. 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 • 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 • 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

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