From gene to disease; from BRCA1 or BRCA2 to breast cancer

Hereditary breast cancer is a heterogeneous syndrome, both phenotypically and genetically. It affects about 5% of all breast cancer patients. The presence of ovarian cancer or breast cancer in males defines important subtypes. BRCA1 and BRCA2 are involved in all hereditary breast cancer syndromes in varying degrees. Both genes confer strongly elevated breast and ovarian cancer risks in mutation carriers, but these risks may be subject to modifying effects by other factors (genetic and/or environmental) at the individual level. In the Netherlands, DNA testing is offered under the national health insurance programme and has led to the identification of over 500 families with either a BRCA1 or BRCA2 mutation. The results of the test are being used widely by Dutch women in the decision for or against prophylactic surgery.     

Estimating risk of breast cancer in carriers of BRCA1 and BRCA2 mutations: a meta-analytic approach

Estimates of penetrance (or risk) of breast cancer among BRCA mutation carriers in published studies are heterogeneous, prohibiting direct combined estimates. Estimates of prevalence of BRCA mutations are more homogeneous and could allow combined estimates of prevalence. We propose a combined estimator of penetrance from combined estimates of the prevalence of BRCA mutations in women with and without breast cancer and from the probability of breast cancer by using Bayes' Theorem. The relative risk of having breast cancer with positive family history and the prevalence of positive family history contribute to the combined estimate of penetrance if family history is present. The combined estimate incorporates variation in estimates from different resources. The method is illustrated by using data from Ashkenazi Jewish women unselected for family history and for those with family history. Risks of breast cancer conferred by BRCA1 and BRCA2 mutations are estimated to be 8.39 per cent (6.56, 10.68 per cent) and 2.66 per cent (1.85, 3.82 per cent) by 40 years old, and 47.45 per cent (37.39, 57.72 per cent) and 31.85 per cent (23.72, 41.26 per cent) by 75 years old, respectively. For those with family history, risks of breast cancer conferred by BRCA mutations appear to be higher.     

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

Objectives

To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed “BRCA”) testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation–positive individuals, compared with no testing. Female BRCA mutation–positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy.

BRCA1 and BRCA2 gene mutations and risk of breast cancer. Public health perspectives.

CONTENT: Breast cancer is the most common cancer and the second most common cause of cancer death among U.S. women. In 1998, about 178,700 new cases will be diagnosed and 43,500 women will die from the disease. Mutations in the BRCA1 gene, which was cloned in 1994 and is located on chromosome 17q, have been identified as causes of predisposition to breast, ovarian, and other cancers. A second breast cancer gene, BRCA2, has been localized to chromosome 13q. Using inferential procedures, the overall carrier frequency of BRCA1 gene mutations has been estimated at 1 in 500 in the general U.S. population. Recent studies have indicated that the carrier frequency of a specific BRCA1 allele, the 185delAG mutation, may be as high as 0.8% to 1% among women of Ashkenazi Jewish descent. CONCLUSIONS: Due to the proliferation of laboratories offering genetic tests for breast cancer susceptibility, their appropriate use in public health needs careful scrutiny. Several issues are raised when such genetic tests are considered for population-based prevention programs for breast cancer. Public health agencies, such as the Centers for Disease Control and Prevention, are important to monitoring and evaluating genetic testing done outside of research protocols. If genetic tests for breast cancer are to be incorporated into future prevention programs, evaluation is needed of whether the testing can have the intended effect.     

乳腺癌中BRCA1基因突变与雌激素受体的关系

目的探讨遗传性乳腺癌与卵巢癌易感基因(Hereditarybreastandovariancancersusceptibilitygene,BRCA1)基因突变、雌激素受体(Estrogenreceptor,ER)在乳腺癌中的作用以及二者之间的关系。方法选取64例乳腺癌患者标本作研究组,另取10例非癌乳腺组织标本作对照组。利用PCR-SSCP法和直接测序法检测BRCA1基因突变情况;利用SP(链霉菌抗生物素蛋白-过氧化物酶链接法)二步法检测ER,比较ER阳性组与ER阴性组BRCA1突变情况。结果10例非乳腺癌组织未检测出BRCA1基因突变。64例乳腺癌标本中检出BRCA1基因突变6例,突变率为9.4%。突变发生在5、12、17外显子上,均为错义突变,ER阳性44例,阳性率为68.75%(44/64)。ER阳性组中只有1例BRCA1突变(1/44),ER阴性组中有5例检出BRCA1突变(5/20),两组比较BRCA1突变率有显著差异性(P>0.05)。结论广西乳腺癌与BRCA1基因突变有关,BRCA1突变与雌激素受体有关,BRCA1基因突变病人雌激素阴性状态比非BRCA1基因突变病人多。     

上皮卵巢癌患者BRCA1/2和KRAS基因突变与预后的相关性

目的探讨上皮卵巢癌患者BRCA1/2和KRAS基因突变与预后的相关性,为上皮卵巢癌的治疗和预后提供理伦依据。方法选取2013年9月-2016年11月在该院产科确诊的70例上皮卵巢癌患者为研究对象,对其进行BRCA1/2和KRAS基因突变分析,并根据基因突变结果分为非突变BRCA1/2组、突变BRCA1/2组,非突变KRAS组、突变KRAS组。分析非突变BRCA1/2组、突变BRCA1/2组,非突变KRAS组、突变KRAS组的PFS、OS、3年生存率及临床特征资料。结果 BRCA1/2基因突变率为32.9%,KRAS基因突变率为8.7%;BRCA1/2、KRAS基因突变情况与分化程度、手术病理分期、细胞学分级、有无转移无相关性,差异无统计学意义(χ~2=0.88、0.96、1.01、1.13,0.97、1.24、2.11、1.01,P0.05);BRCA1/2、KRAS基因突变组对化疗敏感度高于非BRCA1/2、KRAS基因突变组,差异有统计学意义(χ~2=18.45、21.56,P0.05);BRCA1/2、KRAS基因突变组PFS、OS、3年生存率均高于BRCA1/2、KRAS基因非突变组,差异有统计学意义(χ~2=23.64、19.87、21.68,16.54、21.47、19.37,P0.05)。结论 BRCA1/2、KRAS基因突变使上皮卵巢癌患者对化疗药物敏感,预后较好,了解BRCA1/2、KRAS基因突变情况对上皮卵巢癌早期诊断及预后治疗具有重要意义。     

#18 Gynecologic surgeries and risk of ovarian cancer in carriers and non-carriers of the BRCA1 and BRCA2 ashkenazi founder mutations

PURPOSE: Case-control and cohort studies have established that gynecologic surgeries reduce the risk of developing ovarian cancer. It is not clear whether these surgeries also reduce risk in BRCA1 and BRCA2 mutation carriers. We studied Jewish women with incident ovarian cancer and tested for an Ashkenazi founder mutation (185 delAG and 5382insC in BRCA1 and/or 6174delT in BRCA2) to assess risk of ovarian cancer following gynecologic surgery.METHODS: Cases were identified in a population-based case-control study between 1994 and 1999. Controls were selected from the Central Population Registry and were matched to the cases based on age (within 2 years), area of birth, and place and length of residence in Israel. Excluding subjects reporting a bilateral oophorectomy, we tested 840 cases and 751 controls for the founder mutations. There were 244 (29%) cases that tested positive for BRCA1 and BRCA2, and 13 (1.7%) controls that tested positive. We used conditional logistic regression to estimate odds ratios (ORs) for developing ovarian cancer following selected gynecologic surgeries.RESULTS: Overall, gynecologic surgeries reduced the risk of ovarian cancer by 45% compared to women never having a gynecologic surgery (odds ratio (OR) = 0.55, 95% Confidence Interval (95% CI) = 0.44–0.70) after adjusting for age, ethnicity, parity, and oral contraceptive use. The risk estimate for BRCA1 and BRCA2 mutation carriers with a gynecologic surgery compared to the controls was also protective (OR = 0.51, 95% CI = 0.32–0.81).CONCLUSION: Israeli women who are carriers or non-carriers of mutations in BRCA1 and/or BRCA2 appear to benefit from a reduced risk of ovarian cancer following a gynecologic surgery.     

Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population

To date, two major familial breast cancer predisposition genes, BRCA1 and BRCA2, have been identified with hundreds of germ-line mutations, accounting for 5--10% of all breast cancer and 40--60% of all inherited breast cancer. Unexpectedly elevated incidence of breast cancer, especially in the older age classes, was observed in a Western Finnish region representing a relatively homogeneous population. This study was designed to test the hypothesis that there are inherited BRCA1 or BRCA2 mutations, which confer variable and/or age-dependent penetrance on carriers. Expecting a founder effect, we searched for geographical clustering of breast cancer cases and searched for associations between the affected phenotype and shared genomic segments in the BRCA1 and BRCA2 genomic regions. Our haplotype association study did not reveal any founder effects for either BRCA1 or BRCA2. However, there were two mutations prevalent in this geographical area with minor founder effects, BRCA2 T8555G and 999del5. This is one of the few geographically ascertained, population-based studies that indicate an overall frequency of BRCA1 and BRCA2 mutations at about 2--3% in all breast cancer cases. The geographical clustering of breast cancer cases was not explained by BRCA1 or BRCA2 genes.     

Cost-effectiveness of different strategies to prevent breast and ovarian cancer in German women with a BRCA 1 or 2 mutation

Background

Women with a BRCA1 or BRCA2 mutation are at increased risk of developing breast and/or ovarian cancer. This economic modeling study evaluated different preventive interventions for 30-year-old women with a confirmed BRCA (1 or 2) mutation.

Methods

A Markov model was developed to estimate the costs and benefits [i.e., quality-adjusted life years (QALYs), and life years gained (LYG)] associated with prophylactic bilateral mastectomy (BM), prophylactic bilateral salpingo-oophorectomy (BSO), BM plus BSO, BM plus BSO at age 40, and intensified surveillance. Relevant input data was obtained from a large German database including 5902 women with BRCA 1 or 2, and from the literature. The analysis was performed from the German Statutory Health Insurance (SHI) perspective. In order to assess the robustness of the results, deterministic and probabilistic sensitivity analyses were performed.

Results

With costs of €29,434 and a gain in QALYs of 17.7 (LYG 19.9), BM plus BSO at age 30 was less expensive and more effective than the other strategies, followed by BM plus BSO at age 40. Women who were offered the surveillance strategy had the highest costs at the lowest gain in QALYs/LYS. In the probabilistic sensitivity analysis, the probability of cost-saving was 57% for BM plus BSO. At a WTP of 10,000 € per QALY, the probability of the intervention being cost-effective was 80%.

Conclusions

From the SHI perspective, undergoing BM plus immediate BSO should be recommended to BRCA 1 or 2 mutation carriers due to its favorable comparative cost-effectiveness.

     

Measuring women's preferences for breast cancer treatments and BRCA1/BRCA2 testing

In establishing decision models in the treatment and prevention of breast cancer, it is important to evaluate patients' preferences for such interventions. The objectives of the present study were: (i) to characterize women's preferences for breast cancer treatments and BRCA1/BRCA2 testing, using the rating scale and standard gamble techniques; and (ii) to identify factors associated with these quality of life indices. Data were collected from women with breast cancer (n = 60), high-risk relatives of women with breast cancer (n = 58), and women in the general population (n = 51). Regardless of group membership, participants favoured treatment and prevention options that involved minimal physical invasiveness. Women with breast cancer rated lumpectomy and radiation treatment more highly than high-risk relatives and women in the general population. Preferences did not differ according to participants' intentions to undergo BRCA testing. Age was the only demographic variable associated with health state preferences. These findings hold implications for the application of patient preferences to clinical decision making. This revised version was published online in June 2006 with corrections to the Cover Date.     

Epigenetic modulation of BRCA1 and BRCA2 gene expression by equol in breast cancer cell lines

S-Equol is a metabolite resulting from the conversion of daidzein, a soya phyto-oestrogen, by the gut microflora. The potential protective effects of equol in breast cancer are still under debate. Consequently, we investigated the effects of equol on DNA methylation of breast cancer susceptibility genes (BRCA1 and BRCA2) and oncosuppressors in breast cancer cell lines (MDA-MB-231 and MCF-7) and in a dystrophic breast cell line (MCF-10a) following exposure to S-equol (2?μm) for 3 weeks. We demonstrated by quantitative analysis of methylated alleles a significant decrease in the methylation of the cytosine phosphate guanine (CpG) islands in the promoters of BRCA1 and BRCA2 after the S-equol treatment in MCF-7 and MDA-MB-231 cells and a trend in MCF-10a cells. We also showed that S-equol increases BRCA1 and BRCA2 protein expression in the nuclei and the cytoplasm in MCF-7, MDA-MB-231 and MCF-10a cell lines by immunohistochemistry. The increase in BRCA1 and BRCA2 proteins was also found after Western blotting in the studied cell lines. In summary, we demonstrated the demethylating effect of S-equol on the CpG islands inside the promoters of BRCA1 and BRCA2 genes, resulting in an increase in the level of expressed oncosuppressors in breast cancer cell lines.     

Testing for the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes: a decision analysis.

OBJECTIVE: The authors developed a Markov decision model to evaluate the health implications of testing for mutations in the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes. Prophylactic measures considered included various combinations of immediate and delayed bilateral mastectomy and oophorectomy or taking no action. METHODS: The model incorporated the likelihood of developing breast and/or ovarian cancer, survival, and quality of life. Parameter values were taken from public databases, the published literature, and a survey of cancer experts. Outcomes considered were additional life expectancy and quality-adjusted life years (QALYs). Results are reported for 30-year-old cancer-free women at various levels of hereditary risk. RESULTS AND CONCLUSIONS: The vast majority of women will not benefit from testing because their pre-test risks are low and surgical prophylaxis is undesirable. However, women who have family histories of early breast and/or ovarian cancer may gain up to 2 QALYs by allowing genetic testing to inform their decisions.     

Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study.

We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out.     

Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations

In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.