Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families

Abstract

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

“…The literature is not unanimous about the predictive value of multiple primary (ipsilateral or contralateral) breast cancers for finding a mutation. Our results are in agreement with the studies of Bergthorsson et al (2001), de la Hoya et al (2002 and Ford et al (1998); however, others failed to demonstrate such a predictive value (Couch et al, 1997;Steinmann et al, 2001). Male breast cancer in combination with a family history of breast/ovarian cancer was indicative of finding a BRCA2 mutation (P ¼ 0.002), which is consistent with a recent population-based British study (Basham et al, 2002).…”

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

“…Inherited mutations of some of them predispose to breast neoplasm. For example, mutations of BRCA-1 and BRCA-2 are found in approximately 50% and 30%, respectively, of families predisposed to breast cancer (Ford et al, 1998). Somatic p53 mutations are found in about 35% of sporadic and 85% of familial breast cancers (Crook et al, 1998), and germline alterations of p53 are associated with a predisposition to several cancers, including breast cancer (the Li-Fraumeni syndrome).…”

Modifiers of risk of hereditary breast cancer

“…Other methods are used which depend on the reporting of cancers by family members. The lifetime risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation is estimated to be as high as 80% -or roughly 10 times greater than that of the general population -but several estimates are lower (Ford et al, 1998;Risch et al, 2001;Antoniou et al, 2003;King et al, 2003). In a cohort of 76 BRCA1 mutation carriers from Rotterdam, eight invasive cancers were detected during 318 person-years of follow-up (Meijers-Heijboer et al, 2001) -an annual incidence of 2.5%.…”