Informed consent for BRCA1 and BRCA2 testing

While the cloning of BRCA1 and BRCA2 in 1994 and 1995 engendered great enthusiasm from cancer patients, their families and physicians, concerns about potential problems faced by those undergoing genetic testing were also evident. Although much can be learned from previous research on informed consent for testing and research for predictive genetic testing in diseases other than cancer, there are some specific issues related to cancer that make the questions more pressing, more difficult, and of larger social concern. Organizations such as the National Advisory Council for Human Genome Research, the American Society for Human Genetics, the American Society of Clinical Oncology and the Task Force for Genetic Testing have presented recommendations about informed consent for cancer susceptibility testing. However, many unanswered questions remain concerning the informed consent process. This review provides background on informed consent, summarizes studies that have been conducted in the area of genetic testing, with a focus on testing for BRCA1 and BRCA2, and details recommendations for achieving informed consent for genetic testing for cancer susceptibility and research on cancer genetics.     

Functional Domains of the BRCA1 and BRCA2 Proteins

The BRCA1 and BRCA2 genes encode large unrelatedproteins that presumably function as tumor suppressorsin normal epithelial cells of the breast. However, theprimary amino acid sequences of these proteins provide few insights into the mechanisms bywhich BRCA1 and BRCA2 inhibit tumor development.Nevertheless, recent studies have uncovered manysimilarities in the biological properties of BRCA1 andBRCA2, raising the prospect that these proteins mayfunction in a common pathway of tumor suppression andthat inactivation of either gene may represent anequivalent step in the development of breast cancer. Several lines of evidence now suggest a rolefor BRCA1 and BRCA2 in the cellular response to DNAdamage, possibly by virtue of their relationship withproteins required for the recombinational repair of double-strand DNA breaks. Accordingly, the lossof BRCA1 or BRCA2 function might accelerate tumordevelopment by allowing cells to accumulate DNA lesionsthat are potentially oncogenic.     

Expression of BRCA1 and BRCA2 in Normal and Neoplastic Cells

Current evidence strongly supports a role forthe breast cancer susceptibility genes, BRCA1 and BRCA2, in both normal development and carcinogenesis.Valuable clues regarding the function of these genes have been garnered through studies of theirpatterns of expression. A central feature of the in vivopattern of BRCA1 and BRCA2 expression is that each ofthese putative tumor suppressor genes is expressed at maximal levels in rapidly proliferatingcells. This feature is consistent with in vitroobservations that BRCA1 and BRCA2 are expressed in acell cycle-dependent manner. This feature is also wellillustrated during mammary gland development wherein theexpression of BRCA1 and BRCA2 is induced in rapidlyproliferating cellular compartments undergoingdifferentiation, such as terminal end buds duringpuberty and developing alveoli during pregnancy.Strikingly, the spatial and temporal patterns of BRCA1and BRCA2 expression are virtually indistinguishableduring embryonic development and in multiple adulttissues despite the fact that these genes areunrelated. These observations have contributed to theemerging hypothesis that these genes function in similarregulatory pathways.     

Screening and Clinical Implications for BRCA1 and BRCA2 Mutation Carriers

In this article, we review the history oftesting for mutations in breast cancer susceptibilitygenes and discuss the current state of testing formutations in BRCA1 and BRCA2 in different clinicalsettings including at-risk individuals and cancerpatients. The risk of breast cancer, other associatedmalignancies and prognosis in carriers of thesemutations are reviewed. A final section includesdiscussion of current recommendations for surveillance andthe need for further research to identify environmentaland genetic factors which modify the risk of developingcancer in mutation carriers.     

BRCA1 and BRCA2 in Breast Cancer Predisposition and Recombination Control

Hereditary predisposition to breast and ovarian cancer is determined in large part by loss-of-function mutations in one of two genes, BRCA1 and BRCA2 . Early discoveries that the two genes function in the control of homologous recombination and the prevention of genomic instability have been strongly supported by subsequent work. Our aim here is to highlight new advances in the study of BRCA1 and BRCA2 , and to place these advances in the context of existing knowledge.     

Nonsurgical Prevention Strategies in BRCA1 and BRCA2 Mutation Carriers

BackgroundFemale carriers of a BRCA1 or 2 germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.SummaryWhile endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, BRCA1-deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in BRCA1-deficient mouse models.Key MessageThe prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers.     

The role of BRCA1 and BRCA2 in prostate cancer

One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men ≤65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.     

The breast surgeon's role in BRCA1 and BRCA2 testing

Five percent to 10% of all women who develop breast cancer carry a hereditary mutation in the genes BRCA1 or BRCA2. Genetic testing is now clinically available, and the results of such testing can dramatically alter a patient's risks for an ipsilateral or contralateral primary breast cancer and ovarian cancer. Therefore, genetic testing will become integral in tailoring surveillance, chemoprevention, and surgical management plans for patients at risk for hereditary cancer syndromes. Such results will also impact the cancer risks for the patient's nuclear and extended family members. Surgeons will play a pivotal role in eliciting personal and family histories from patients, determining which of those histories is suggestive of a germline mutation, facilitating referrals for genetic counseling and testing, and incorporating the results of genetic testing into the patient's short- and long-term management plans.     

Risk management decisions in women with BRCA1 and BRCA2 mutations

Introduction

Pathogenic mutations and variants of uncertain significance (VUS) occur in BRCA1/2 genes.

Functional Characterization of BRCA1 and BRCA2: Clues from Their Interacting Proteins

The familial breast and ovarian cancersusceptibility genes, BRCA1 and BRCA2 have been thesubject of extensive functional analysis studies sincetheir cloning. Clues to their biological role inmaintaining the genomic integrity were provided by studiesthat revealed their interaction with the recombinationrepair protein HsRad51. The first clue of an interactionbetween HsRad51 and BRCA1 came from the colocalization of the characteristic nuclear foci formed bythese two proteins during S phase of the cell cycle. Aninteraction between murine Brca2 and MmRad51 wasdetected by the yeast two hybrid system. Utilizing the yeast two hybrid system and other techniquesseveral other Brca1 and Brca2 interacting proteins havebeen identified like, BARD1, importin-, BIPs, RNApolymerase II holoenzyme, BRAP2 etc. Recently, mutations suggesting a role as a tumorsuppressor have been identified in the BARD1 gene inprimary human tumors. The identification of moleculesthat interact with Brca1 and Brca2 has greatly enhanced our knowledge of how BRCA1 and BRCA2 mayfunction as tumor suppressors.     

散发性乳腺癌中BRCA1和BRCA2基因突变的研究

目的检测BRCA1和BRCA2基因在散发性乳腺癌中的突变情况,探讨BRCA1和BRCA2基因突变与乳腺癌的关系。方法选取2000年12月至2005年9月收治的144例乳腺癌患者标本作实验组,另取非癌乳腺组织标本30例作对照组。用酚-氯仿抽提法提取DNA。针对各个外显子的碱基序列特征,设计有助于筛查基因碱基突变的聚合酶链反应（PCR）引物。每例DNA标本均用PCR扩增BRCA1基因的全部22个外显子和BRCA2基因的exon10和exon14两个外显子。分别将每例外显子的PCR扩增产物进行单链构象多态性分析,对泳动变位或出现异常区带的PCR扩增产物进行DNA测序。结果对照组未检测出BRCA1和BRCA2基因突变,实验组中检测出20例BRCA1基因碱基改变,总突变率为13．9％,其中错义突变率为11．1％。BRCA2基因exon10和exon14未检测出突变。结论BBCA1突变与乳腺癌密切相关,筛查BRCA1基因突变对于中国人群乳腺癌患病风险评估、早期诊断及基因治疗具有重要意义。     

米非司酮调控BRCA1、BRCA2蛋白表达的研究

目的研究米非司酮调控乳腺癌细胞系MCF-7细胞BRCA1和BRCA 2蛋白的表达变化。方法不同浓度米非司酮(0.25、2.5、25和50μmol/L)分别处理人乳腺癌细胞系MCF-7 1d后,应用免疫组化方法检测米非司酮各浓度组和对照组BRCA1、2蛋白表达变化;并通过检测各组平均光密度值,半定量比较BRCA1、2蛋白的表达差异;采用细胞计数的方法比较各组细胞核BRCA1、2蛋白表达率。结果对照组细胞中BRCA1蛋白呈细胞胞浆阳性;米非司酮0.25μmol/L组主要表达于胞浆,少量细胞呈核阳性;米非司酮2.5μmol/L组细胞核和细胞浆均为阳性。对照组细胞中,BRCA2蛋白主要表达于细胞胞浆中;米非司酮各组细胞胞浆和细胞核中均有表达。平均光密度值比较显示,与其他各组相比较,2.5μmol/L组BRCA1和BRCA2蛋白表达量最高,显著高于其他各组(P均0.05)。对照组细胞核中BRCA1和BRCA2蛋白阳性表达率分别为(19.58±6.90)%和(36.60±3.01)%,均显较低,且显著低于米非司酮各个组(P均0.05);2.5μmol/L组和25μmol/L组细胞核中BRCA1蛋白阳性表达率显著高于0.25μmol/L组和50μmol/L组,差异有统计学意义(P均0.05)。结论米非司酮在蛋白水平上上调乳腺癌细胞系MCF7细胞中BRCA1、BRCA2的表达,但不同浓度米非司酮促蛋白表达模式不同;米非司酮可以促进MCF7细胞中BRCA1、BRCA2蛋白的入核表达。     

BRCA1 and BRCA2 germ-line mutations and oral contraceptives: to use or not to use

Approximately 10% of the cases of breast cancer and invasive ovarian cancer are hereditary, occurring predominantly in women with germ-line mutations in the BRCA1 or BRCA2 gene. In deciding whether women with germ-line mutations in the BRCA1 gene should use oral contraceptives a possible increase in the risk of breast cancer needs to be weighed against the convenience of this means of birth control and its potential to reduce the risk of ovarian cancer. In women with BRCA2 mutations, oral contraceptive use has not been associated with an increased risk of breast cancer and does have the potential to reduce the risk of ovarian cancer. Prophylactic surgical options and intensified surveillance should, of course, be discussed with these patients.     

Perspective on BRCA1

In a very real sense, the search for a breast cancer susceptibility gene reflects the rapid evolution of molecular genetics as a field and the power of molecular technology to accelerate the pace of discovery. This search began with the study of blood proteins through biochemical analysis; the number of loci accessible was limited, and very few consistent results were obtained (1). Then came recombinant DNA technology. The number of available markers, and the information they provide, has grown rapidly over the years. The same is true for the development of new, high-throughput genotyping methods and associated informatics systems and statistical methods, making gene mapping more feasible. For BRCA1, it took five years and 183 markers to identify the chromosomal location as 17q21 (2). It took an additional four years before BRCA1 was cloned (3). In contrast, BRCA2 was localized to chromosome 13q12-13 two months before the cloning of BRCA1 was reported; less than two years later, BRCA2 was cloned (4,5). Characterization of these two genes is still underway, in part, because of unanticipated complexity. This complexity plays out at multiple levels, including the relationship between phenotype and genotype within and between the populations studied, biological function(s), and social consequences. The reviews presented in this issue reflect the breadth of impact that the discovery of the BRCA genes has had on science, medicine, and law. As with most great discoveries, the identification of BRCA1 has forced us to question the fundamentals of our belief systems: what is a mutation, what is a tumor suppressor, what is righteous, and what is ethical?     

米非司酮调控乳腺癌细胞中BRCA基因表达变化的研究

目的研究米非司酮处理乳腺癌细胞系T47D后,BRCA1和BRCA 2在mRNA水平的表达变化。方法使用不同浓度米非司酮(0.25、2.5、25μmol/L)分别处理人乳腺癌细胞系T47D 1d后,应用荧光实时定量聚合酶链反应(Realtime-PCR)的方法检测各浓度组和对照组BRCA1、2基因的表达差异。结果不同浓度米非司酮(0.25、2.5、25μmol/L)分别处理人乳腺癌细胞系T47D 1 d后,BRCA1、2基因在mRNA水平上表达均降低。米非司酮25μmol/L组分别与对照组和0.25μmol/L组比较,BRCA1基因在mRNA水平上表达均降低,且具有统计学差异(P<0.05)。与对照组比较,米非司酮2.5μmol/L组BRCA2基因在mRNA水平上表达降低,且具有统计学差异(P<0.05);米非司酮25μmol/L组分别与对照组和0.25μmol/L组比较,BRCA2基因在mRNA水平上表达降低,均具有统计学差异(P<0.01)。结论在乳腺癌细胞中,米非司酮在转录水平上调控BRCA1、2基因的表达。     

BRCA1和BRCA2在胶东半岛地区女性散发性乳腺癌中的表达研究

Objective To study the expression and clinical significance of BRCA1 and BRCA2 in sporadic breast cancer in women of Jiaodong peninsula. Methods Immunohistochemistry and tissue array were used to detect the expression of BRCA1 and BRCA2 in 100 cases of sporadic breast cancer and 30 cases of benign breast tumor in women of Jiaodong peninsula. Results ① The expression rate of BRCA1 and BRCA2 was 49% (49/100) and 50% (50/100) in breast cancer, 80% (24/30) and 83.33% (25/30) in benign breast lesions respectively. The expression rate of BRCA1 and BRCA2 in breast cancer was lower than that in benign breast lesions (P<0.05). ② The expression of BRCA1 and BRCA2 was uncorrelated with factors such as tumor size, lymphatic metastases, age and menopause or not(P>0.05). ③ There was no dependency between the expression of BRCA1 and BRCA2 (P> 0. 05). Conclusions The expression rate of BRCA1 and BRCA2 in breast carcinoma in women of Jiaodong peninsula was lower than that in benign breast lesions, suggesting that the expression of BRCA1 and BRCA2 was related to the occurrence of sporadic breast carcinoma in women of Jiaodong peninsula. However, the role of BRCA1 and BRCA2 in the genesis and development of the breast carcinoma is independent.