Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.

Abstract

Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a populationbased series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency ofthe susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by chance. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.

Risk of cancer in relatives of testicular cancer patients

“…Testicular cancer patients may be less likely to know of cancers in the grandparents than in their first-degree relatives. On the other hand, it may be that there is a deficit of factors predisposing to common (Kaldor et al, 1987;Fossa et al, 1990;Moller H. et al, 1993;Jacobsen et al, 1993;van-Leeuwen et al, 1993 (Newman et al, 1988;Claus et al, 1991;Iselius et al, 1991Iselius et al, , 1992. If we set the gene frequency to 1:200-1:300, the expected number of breast(-ovarian) families would be 3-5.…”

An epidemiologic approach to gene‐environment interaction

“…Late age at first pregnancy (>30 years) is known to be associated with increased breast cancer risk [Kelsey, 1979] and may have either nongenetic or genetic origins (e.g., genetic syndromes involving infertility). Several investigators have demonstrated that susceptibility to breast cancer is increased in some families by an autosomal dominant gene [Newman et al, 1988;Williams and Anderson, 1984;Go et al, 1983], but the genetic form of the disease appears to affect only a minority of patients (approximately 4%) [Newman et al, 1988]. Some women, even in high-risk families, appear to inherit susceptibility from their mothers and transmit it to their daughters without ever becoming affected themselves.…”

Analysis of breast cancer susceptibility genesBRCA1 andBRCA2 in Thai familial and isolated early-onset breast and ovarian cancer

“…Approximately, five to ten percent of all breast and ovarian cancers are due to genetic predisposition with autosomal dominant transmission (Newman et al, 1988;Claus et al, 1991;Schildkraut et al, 1989). Two major breast and ovarian cancer susceptibility genes, BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), have been identified (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996).…”