Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years.

Although well studied in families at high-risk, the roles of mutations in the BRCA1 and BRCA2 genes are poorly understood in breast cancers in the general population, particularly in Black women and in age groups outside of the very young. We examined the prevalence and predictors of BRCA1 and BRCA2 mutations in 1,628 women with breast cancer and 674 women without breast cancer who participated in a multicenter population-based case-control study of Black and White women, 35 to 64 years of age. Among cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in White (2.9%) versus Black (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in Black (2.6%) versus White (2.1%) cases. Numerous familial and demographic factors were significantly associated with BRCA1 and, to a lesser extent, BRCA2 carrier status, when examined individually. In models considering all predictors together, early onset ages in cases and in relatives, family history of ovarian cancer, and Jewish ancestry remained strongly and significantly predictive of BRCA1 carrier status, whereas BRCA2 predictors were fewer and more modest in magnitude. Both the combinations of predictors and effect sizes varied across racial/ethnic and age groups. These results provide first-time prevalence estimates for BRCA1/BRCA2 in breast cancer cases among understudied racial and age groups and show key predictors of mutation carrier status for both White and Black women and women of a wide age spectrum with breast cancer in the general population.

BRCA1 and BRCA2 mutations in women from Shanghai China.

Little is known about the frequency of germ-line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 among Asian populations. We investigated the distribution of BRCA1 and BRCA2 germ-line mutations and polymorphisms in a cohort of women from Shanghai, China. Study subjects totaled 1306, and included 645 women with breast cancer, 342 women with benign breast disease, and 319 unaffected controls, born between 1924 and 1958, selected from women enrolled in a randomized trial of Breast Self-Examination in Shanghai, China. Women were selected without regard to family history of breast or ovarian cancer. All of the coding regions and exon-intron boundaries were screened. Data were analyzed with respect to age at diagnosis, and family history of breast and ovarian cancer. The prevalence of known disease-associated mutations in women with breast cancer was 1.1% each, for BRCA1 and BRCA2. Among breast cancer cases with a family history of breast or ovarian cancer, 8.1% and 2.7% carried likely BRCA1 and BRCA2 disease-associated mutations, respectively. Overall, these results suggest that inherited susceptibility to breast cancer due to germ-line BRCA1/2 mutations among women with a family history of breast cancer is comparable between women from Shanghai and Caucasian women of Western European descent. Most alterations observed appear unique to the Chinese population, suggesting a resource that will be useful for assessing risk among both Chinese women and United States women of Chinese descent.

Androgen receptor (CAG)n and (GGC)n polymorphisms and breast cancer risk in a population-based case-control study of young women.

The androgen receptor (AR) is involved in the regulation of hormone-responsive genes and, as such, variation within the gene is hypothesized to play a role in breast cancer susceptibility. We therefore assessed the relationship between AR repeat variation and breast cancer in young women from the general population. Women diagnosed with breast cancer before age 45 years and age-matched controls, all participants in a population-based case-control study of breast cancer, were assessed for length variation in the (CAG)(n) and (GGC)(n) AR repeats within the AR gene. Results were generated from 524 cases and 461 controls. As per previous studies, (CAG)(n) repeat lengths of <22 were classified as short (S), and those of > or =22 were classified as long (L). For (GGC)(n) repeats, those < 17 were classified as short, and those > or = 17 were classified as long. Women with a cumulative (CAG)(n) repeat size of > or =43 showed a modest increase in risk for breast cancer [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7]. Women with a (GGC)(n) long (L) allele and those with a > or =33 cumulative repeat size had a decreased risk of breast cancer (OR, 0.7; 95% CI, 0.5-0.9). Among women homozygous for the (CAG)(n) short (S) allele and those with any (GGC)(n) L allele, an increased risk of breast cancer in relation to ever use of oral contraceptives [OCs; OR = 1.9 (95% CI, 1.0-3.6) and OR = 1.7 (95% CI, 0.9-3.5), respectively] was observed. An increased risk for OC use, however, was not observed among women with the CAG L or GGC S allele. This study, one of the first to examine both (CAG)(n) and (GGC)(n) in a population-based study for its relation to breast cancer risk, suggests a reduced risk in young women with (GGC)(n) repeat lengths of > or =17. In addition, these data suggest that AR repeat length may be partly responsible for the increased risk for early-onset breast cancer in women who use OCs, although these findings need replication in other populations.

BRCA1 and BRCA2 sequence variants in Chinese breast cancer families.

A series of 45 high-risk breast cancer patients, consisting of 25 affected individuals from 16 families in China with at least two cases of breast cancer and 20 cases of breast cancer diagnosed under age 35 without reported family history, were studied for germline mutations of the BRCA1 and BRCA2 genes. Thirteen of the 16 families contained at least one case diagnosed under age 50. Three distinct protein truncating sequence variants, likely to be disease-associated, were identified: two novel mutations in BRCA1 (1584G>T and 5028delC), and a previously reported mutation in BRCA2 (7883delTTAA). Additional sequence variants identified included common polymorphisms, and several variants of unknown clinical significance, including a novel BRCA1 alteration. Based on models for predictive testing using allele frequencies and risks estimated in Western populations, our results suggest that BRCA1/2 mutations account for a somewhat smaller fraction of breast cancer cases in Tianjin than in the Caucasian populations studied. This difference could be the result of a lower penetrance of BRCA1/2 mutations due to the surrounding environmental and hormonal milieu, or a lower frequency of mutations in this population. Larger, more detailed, studies will be necessary to determine which factors underlie this difference.