Re: On the use of familial aggregation in population-based case probands for calculating penetrance.

JNCI Journal of the National Cancer Institute (Impact Factor: 15.16). 02/2003; 95(1):76-7; author reply 77-8. DOI: 10.1093/jnci/95.1.76
Source: PubMed
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    ABSTRACT: A family history of breast cancer poses higher risks for Jewish versus non-Jewish women, particularly for early-onset breast cancer. This appears to be due in large part to the high prevalence (2.5%) of three BRCA1 and BRCA2 founder mutations in Ashkenazi Jews. About 4 to 8% of non-Jewish male breast cancer cases versus 19% of Jewish male breast cancer cases carry germline BRCA mutations. Jewish women are disproportionately impacted by BRCA mutations throughout life, with a 10% carrier rate for breast cancer diagnosed at any age and a 21 to 30% carrier rate for breast cancer diagnosed by age 40. Comparable rates in non-Jewish populations are 6.1% for breast cancer diagnosed before age 50. Lifetime penetrance estimates based on genotyping of probands have ranged widely in Jewish and non-Jewish populations. However, a study of 1008 Jewish women with breast cancer which extended genotyping to relatives found high penetrance rates with considerably smaller standard errors. This study and studies of early-onset incident breast cancer in non-Jews have found that at least half of high-risk cases would be missed by family history screening alone. While the carrier rate in non-Jewish populations is too low to consider genetic screening, the carrier rate in Ashkenazi Jews is high and genetic screening poses fewer technical barriers. The high genetic attributable cancer risks of Ashkenazi BRCA founder mutations, the sobering lethality of ovarian and early onset breast cancers, and the increasing clarity about effectiveness of medical interventions make imperative further dialogue and research to keep guidelines for genetic screening up to date.
    Familial Cancer 02/2004; 3(3-4):249-57. DOI:10.1007/s10689-004-9550-2 · 1.62 Impact Factor
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    ABSTRACT: BRCA1 and BRCA2 mutation carriers have elevated risks of breast and ovarian cancers. The risks for cancers at other sites remain unclear. Melanoma has been associated with BRCA2 mutations in some studies, however, few surveys have included non-melanoma skin cancer. We followed 2729 women with a BRCA1 or BRCA2 mutation for an average of 5.0 years. These women were asked to report new cases of cancer diagnosed in themselves or in their family. The risks of skin cancer were compared for probands with BRCA1 and BRCA2 mutations. Of 1779 women with a BRCA1 mutation, 29 developed skin cancer in the follow-up period (1.6%). Of the 950 women with a BRCA2 mutation, 28 developed skin cancer (3.0%) (OR = 1.83 for BRCA2 versus BRCA1; 95% CI 1.08-3.10; P = 0.02). The odds ratio for basal cell carcinoma was higher (OR = 3.8; 95% CI 1.5-9.4; P = 0.002). BRCA2 mutation carriers are at increased risk for skin cancer, compared with BRCA1 carriers, in particular for basal cell carcinoma.
    Familial Cancer 12/2010; 9(4):489-93. DOI:10.1007/s10689-010-9377-y · 1.94 Impact Factor
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    ABSTRACT: In case-control studies of inherited diseases, participating subjects (probands) are often interviewed to collect detailed data about disease history and age-at-onset information in their family members. Genotype data are typically collected from the probands, but not from their relatives. In this article, we introduce an approach that combines case-control analysis of data on the probands with kin-cohort analysis of disease history data on relatives. Assuming a marginally specified multivariate survival model for joint risk of disease among family members, we describe methods for estimating relative risk, cumulative risk, and residual familial aggregation. We also describe a variation of the methodology that can be used for kin-cohort analysis of the family history data from a sample of genotyped cases only. We perform simulation studies to assess performance of the proposed methodologies with correct and mis-specified models for familial aggregation. We illustrate the proposed methodologies by estimating the risk of breast cancer from BRCA1/2 mutations using data from the Washington Ashkenazi Study.
    Biometrics 04/2006; 62(1):36-48. DOI:10.1111/j.1541-0420.2005.00442.x · 1.52 Impact Factor


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