International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers

Several options for cancer prevention are available for women with a BRCA1 or BRCA2 mutation, including prophylactic surgery, chemoprevention and screening. The authors report on preventive practices in women with mutations from 9 countries and examine differences in uptake according to country. Women with a BRCA1 or BRCA2 mutation were contacted after receiving their genetic test result and were questioned regarding their preventive practices. Information was recorded on prophylactic mastectomy, prophylactic oophorectomy, use of tamoxifen and screening (MRI and mammography). Two thousand six hundred seventy-seven women with a BRCA1 or BRCA2 mutation from 9 countries were included. The follow-up questionnaire was completed a mean of 3.9 years (range 1.5-10.3 years) after genetic testing. One thousand five hundred thirty-one women (57.2%) had a bilateral prophylactic oophorectomy. Of the 1,383 women without breast cancer, 248 (18.0%) had had a prophylactic bilateral mastectomy. Among those who did not have a prophylactic mastectomy, only 76 women (5.5%) took tamoxifen and 40 women (2.9%) took raloxifene for breast cancer prevention. Approximately one-half of the women at risk for breast cancer had taken no preventive option, relying solely on screening. There were large differences in the uptake of the different preventive options by country of residence. Prophylactic oophorectomy is now generally accepted by women and their physicians as a cancer preventive measure. However, only the minority of women with a BRCA1 or BRCA2 mutation opt for prophylactic mastectomy or take tamoxifen for the prevention of hereditary breast cancer. Approximately one-half of women at risk for breast cancer rely on screening alone.     

X chromosome inactivation pattern in BRCA gene mutation carriers

An association of preferential X chromosome inactivation (XCI) with BRCA gene status and breast/ovarian cancer risk has been reported. We evaluated XCI in a large group of BRCA mutation carriers compared to non-carriers and investigated associations between preferential XCI (?90:10) and age, mutated gene, cancer development and chemotherapy. XCI was analysed by human androgen receptor (HUMARA) assay and pyrosequencing in 437 BRCA1 or BRCA2 mutation carriers and 445 age-matched controls. The distribution of XCI patterns in the two groups was compared by logistic regression analysis. The association between preferential XCI and selected variables was investigated in both univariate and multivariate fashion. In univariate analyses preferential XCI was not significantly associated with the probability of being a BRCA mutation carrier, nor with cancer status, whereas chemotherapeutic regime and age both showed a significant association. In multivariate analysis only age maintained significance (odds ratio, 1.056; 95% confidence interval, 1.016–1.096). Our findings do not support the usefulness of XCI analysis for the identification of BRCA mutation carriers and cancer risk assessment. The increasing preferential XCI frequency with ageing and the association with chemotherapy justify extending the investigation to other categories of female cancer patients to identify possible X-linked loci implicated in cell survival.     

Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers after diagnosis and to determine which factors are predictive of the risk of a second primary breast cancer. PATIENTS AND METHODS: Patients included 491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. RESULTS: The actuarial risk of contralateral breast cancer was 29.5% at 10 years. Factors that were predictive of a reduced risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR], 0.73; 95% CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v 相似文献   

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.     

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.     

Increased level of bleomycin-induced chromosome breakage in ataxia telangiectasia skin fibroblasts

Ataxia telangiectasia (AT) is an autosomal recessive disorder in which increased level of chromosome breakage and specific sensitivity to radiation and carcinogens have been reported. The effect of the radiomimetic drug bleomycin on chromosome breakage has been tested in skin fibroblasts of three patients with AT, two AT obligate heterozygotes, two normal human controls, and one normal amniotic fluid cell culture. Bleomycin in two concentrations (1 and 5 micrograms/ml) was added for 1 hr and cultures were harvested 4 hr later. A significant increase in chromosome damage was found in AT fibroblasts: a higher number of total breaks per cell, affected cells, and breaks per affected cell was found. The heterozygotes did not differ significantly from the controls. Chromosome breakage in skin fibroblasts of AT patients after bleomycin treatment has not been reported before.     

Cancer Incidence in BRCA1 mutation carriers

BACKGROUND: Germline BRCA1 mutations confer a substantial lifetime risk of breast and ovarian cancer, but whether cancer at other sites is increased is less clear. To evaluate the risks of other cancers in BRCA1 mutation carriers, we conducted a cohort study of 11 847 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America. METHODS: The observed cancer incidence was compared with the expected cancer incidence based on population cancer rates. Relative risks (RRs) of each cancer type in BRCA1 carriers relative to risks for the general population were estimated by weighting individuals according to their estimated probability of being a mutation carrier. All statistical tests were two-sided. RESULTS: BRCA1 mutation carriers were at a statistically significantly increased risk for several cancers, including pancreatic cancer (RR = 2.26, 95% confidence interval [CI] = 1.26 to 4.06, P =.004) and cancer of the uterine body and cervix (uterine body RR = 2.65, 95% CI = 1.69 to 4.16, P<.001; cervix RR = 3.72, 95% CI = 2.26 to 6.10, P<.001). There was some evidence of an elevated risk of prostate cancer in mutation carriers younger than 65 years old (RR = 1.82, 95% CI = 1.01 to 3.29, P =.05) but not in those 65 years old or older (RR = 0.84, 95% CI = 0.53 to 1.33, P =.45). Overall, increases in the risk for cancer at sites other than the breast or ovary were small and evident in women (RR = 2.30, 95% CI = 1.93 to 2.75, P =.001) but not in men (RR = 0.95, 95% CI = 0.81 to 1.12, P =.58). CONCLUSIONS: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men. BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women.     

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.     

Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

PURPOSE: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations. EXPERIMENTAL DESIGN: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer. RESULTS: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation. CONCLUSIONS: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.     

Clinical management of BRCA1 and BRCA2 mutation carriers

The cancer susceptibility genes BRCA1 and BRCA2 appear to be responsible for virtually all hereditary breast ovarian families, and a smaller subset of hereditary site-specific breast cancer families. Fortunately, effective strategies have been developed to reduce the risk for the development of breast and ovarian cancer in women with BRCA1/2 mutations, making genetic testing for these mutations an important part of the management at women with a strong family history of these diseases. Here, we review the current evidence for risk reduction strategies and outline future research directions.     

Increased rates of spontaneous sister chromatid exchange in lymphocytes of BRCA2+/- carriers of familial breast cancer clusters

Heterozygous carriers of germ-line mutations of the BRCA2 breast cancer susceptibility gene are predisposed to breast, ovarian, pancreatic and other cancers. The BRCA2 protein is implicated in the maintenance of chromosome stability through its essential function in double-strand DNA repair and recombination. Our previous studies had revealed multiple intrachromosomal rearrangements, duplications, inversions and deletions on 9p23-24 in lymphocytes and fibroblasts of BRCA2+/- members from independently ascertained familial breast cancer clusters. In pursuit of evaluating if there is a subtle genomic instability in BRCA2+/- individuals, we have determined frequencies of spontaneous sister chromatid exchanges (SCEs) in BRCA2 wild-types and BRCA2 mutation carriers of two familial breast cancer clusters. Here, we demonstrate an average increase of 65% of spontaneous SCEs in BRCA2+/- versus BRCA2+/+ family members. In one cluster, the number of metaphases with multiple SCEs was 5-times higher in BRCA2+/- compared to wild-type members, while in the second cluster BRCA2+/- members had 8.9% of metaphases with multiple SCEs compared to a level below detection in BRCA2 wild types. To investigate the correlation between SCE and genomic instability in 9p, we performed fluorescence detection of SCEs and FISH analysis with 9p probes. The frequency of SCE in 9p of BRCA2 mutation carriers was 3-4 fold (P = 0.005) higher compared to BRCA2 wild-types. Collectively, the increased rates of SCE in BRCA2 heterozygous mutation carriers indicate a BRCA2 haploinsufficiency, which might be an important factor for the accumulation of structural chromosomal alterations with the consequence of damage in as yet unidentified genes.     

Bilateral risk-reducing oophorectomy in BRCA1 and BRCA2 mutation carriers

Bilateral risk-reducing oophorectomy (BRRO) is widely used for cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations. BRRO significantly reduces breast cancer risk by approximately 50% and ovarian cancer risk by 85% to 95%, but it may be accompanied by menopausal symptoms, impaired quality of life, and accelerated bone loss. Therefore, decisions regarding the timing of BRRO, the risks and benefits of a simultaneous hysterectomy, and the use of hormone replacement therapy (HRT) must be made in concert with the patient and individualized to their circumstances. However, recent data demonstrate that HRT after BRRO in unaffected premenopausal women does not negate the breast cancer risk reduction that BRRO provides. This article reviews the studies regarding BRRO in BRCA1/2 mutation carriers, with particular focus on the use of HRT.     

Increased breakage of chromosome 1 in lymphocytes of patients with testicular cancer after bleomycin treatment in vitro

Chromosome damage in vitro after bleomycin treatment during the late S and G2 phases of the cell cycle was studied in the peripheral lymphocytes of 19 untreated patients with primary testicular tumours and 22 age-matched healthy men with no excess of cancer incidence in the families. The occurrence of spontaneous chromosome aberrations was not shown to be different in the studied groups. However, in the lymphocytes treated with bleomycin, cancer patients exhibited higher numbers of break events per cell (1.06 versus 0.67, P less than 0.01) and increased frequency of cells with aberrations (55.0 versus 43.0, P less than 0.05) than control group. Aberrant cells of cancer patients had more aberrations than cells of the control sample (1.79 versus 1.53, P less than 0.01). The frequency of chromosome 1 aberrations, often encountered in cancer cells of testicular and other solid tumours, was significantly higher in lymphocytes of patients with testicular cancer (15.0 versus 8.4%, P less than 0.0001), the long arm of this chromosome being predominantly affected (12.0 versus 6.3%, P less than 0.0001). These results support the view that a genome disposed to testicular cancer is less effective in the ability to repair non-specific DNA damage in this region, more susceptible to damage, or both.     

Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers

It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case–control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20–1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99–1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14–1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03–1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79–1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.     

Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers

Women with a BRCA1 or BRCA2 mutation have an elevated risk of breast cancer and of contralateral breast cancer. In this study, we estimate the risk of non-synchronous ipsilateral breast cancer after a diagnosis of breast cancer in BRCA carriers and evaluate the effects of various treatments on this risk. Patients were 396 women with stage I or stage II breast cancer with an intact ipsilateral breast and for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until the first of ipsilateral mastectomy, ipsilateral breast cancer, death or last follow-up. The 5-year actuarial risk of ipsilateral breast cancer was 5.8% (95% CI 3.2-8.4%) and the 10-year risk was 12.9% (95% CI 8.7-17.1%). Subjects who received chemotherapy had a significantly lower risk of ipsilateral breast cancer compared to those who did not receive chemotherapy (RR 0.45; 95% CI 0.24-0.84; P = 0.01). Radiotherapy was associated with a reduced risk of ipsilateral breast cancer (RR 0.28; 95% CI 0.12-0.63; P = 0.002). Oophorectomy was associated with a significant reduction in the risk of ipsilateral breast cancer (RR 0.33; 95% CI; 0.13-0.81; P = 0.02). On average, following a diagnosis of breast cancer, the annual risk of ipsilateral breast cancer risk in BRCA mutation carriers is 1.2% per year. For women treated with chemotherapy, radiation therapy or oophorectomy the risk is low, compared to women who did not receive any of these treatments.