During the past decade, progress has been made in localizing and identifying specific genes such as BRCA1 and p16 which when altered can confer a markedly increased susceptibility to relatively common cancers. Although variations at these genes apparently increase risk of cancer at a variety of anatomical sites, there is controversy about the magnitude of these risks. Risks derived from population-based studies have produced lower estimates of risk than those estimated from studies of single large families or series of multiple high-risk families. Whether these differences reflect inherent biases in the methods used for risk estimation or represent the effects of modifying loci segregating in high-risk families is not obvious. Statistical methods for estimation of gene effects are relatively underdeveloped. Additionally, there have been no studies that examine the feasibility of mapping hypothesized modifier loci in the context of a total genome search. This project seeks to examine the efficiency and bias associated with various sampling designs and statistical methods for estimation of cancer risks due to such genes. Monte-Carlo simulation and existing datasets encompassing the three approaches described above will be used for the evaluation of a variety of methods. Several designs for a) testing the effect on risk modification of specific candidate loci; b) detecting the presence of residual genetic effects; and c) examining the power of different sampling designs for genome-wide screens to localize modifier loci also will be examined.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Erickson, Burdette (BUD) W
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International Agency for Research on Cancer
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Brohet, Richard M; Goldgar, David E; Easton, Douglas F et al. (2007) Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25:3831-6
Chang-Claude, Jenny; Andrieu, Nadine; Rookus, Matti et al. (2007) Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 16:740-6
Andrieu, Nadine; Goldgar, David E; Easton, Douglas F et al. (2006) Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98:535-44
Antoniou, A C; Pharoah, P D P; Narod, S et al. (2005) Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet 42:602-3
Antoniou, Antonis C; Goldgar, David E; Andrieu, Nadine et al. (2005) A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol 29:1-11
Thompson, Deborah; Witte, John S; Slattery, Martha et al. (2004) Increased power for case-control studies of single nucleotide polymorphisms through incorporation of family history and genetic constraints. Genet Epidemiol 27:215-24
Sibert, Alexandre; Goldgar, David E (2003) The effect of disease penetrance, family size, and age of onset on family history with application to setting eligibility criteria for genetic testing. Fam Cancer 2:35-42
Thompson, Deborah; Easton, Douglas F; Goldgar, David E (2003) A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73:652-5
Antoniou, Antonis C; Easton, Douglas F (2003) Polygenic inheritance of breast cancer: Implications for design of association studies. Genet Epidemiol 25:190-202
Antoniou, A; Pharoah, P D P; Narod, S et al. (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117-30

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