DESCRIPTION (provided by applicant): The Jerusalem Perinatal Study is a population-based cohort of mothers, fathers and their 92,408 offspring born in 1964-76. Subsets of the cohort may be at risk for cancer through founder mutations in BRCA1, BRCA2, FANCC, ATM, BLM, APC and other genes. During 1998-2002 we traced 98% of the offspring (median age 30) and 94% of their mothers and linked them to Israel's Population Registry and its Cancer Registry. We found 642 first primary malignancies in offspring and 2516 in mothers, including 1065 cases of breast cancer. Jewish women from Morocco showed less breast cancer than expected. Ancestries from Iraq, lran/Afghanistan and other West Asian countries were associated with an increased risk of breast cancers in mothers. Daughters with these ancestries experienced more breast cancer, and a specific birth defect was observed in their families. West Asian ancestry also predicted lymphomas in offspring. Other familial associations were observed for myeloid leukemia in offspring. Preeclampsia was a risk factor for cancers of breast, ovary, stomach, lung/larynx and kidney in mothers, as well as for cardiovascular mortality. We found the wives of elderly fathers more at risk for preeclampsia. These and other findings in the cohort have suggested that this population may be at increased risk for de novo mutation in men's spermatogonia, or defects in meiosis. They raise questions about paternal susceptibility to cancer in relation to their potential for reproduction. In continuing the project for a further five years, we propose to add 40,000 fathers to the study, tracing and ascertaining cancer incidence in them, and updating our knowledge of cancer and mortality in mothers and offspring. We will construct family sets and continue to describe and analyze associations of breast cancer in mothers, common cancers in either parents, pediatric cancers, complications of pregnancy and characteristics of newborns (e.g. birth weight and birth defects), both in individuals and families. Further analyses of breast cancer will focus on countries of origin and attempt to identify interactions with other risk factors that might help elucidate whether the risk in migrants from West Asia is due to a unique genetic component or to special environments experienced by Asian immigrants.
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