BRCA1、BRCA2基因与乳腺癌、卵巢癌多发家族

目前研究普遍认为，BRCA1、BRCA2基因属抑癌基因，这些基因的某些突变型的携带者，患乳腺癌、卵巢癌等恶性肿瘤的危险性显著增高。本文介绍了BRCA1、BRCA2基因定位和克隆后，近年来对上述基因相关家族的特声、、基因外显年、抑癌机制、基因突变热点、突变类型的种族特异性等方面的研究进展，介绍了肿病高度和中反危险家族的划分方法和意义，并分析了今后我国在相关领域深入研究的思路。     

BRCA1,BRCA2基因与乳腺癌,卵巢癌多发家族

目前研究普遍认为,ＢＲＣＡ１,ＢＲＣＡ２基因属抑癌基因,这些基因的某些突变型的携带,患乳腺癌,卵巢癌等恶性肿瘤的危险性显增高,本介绍了ＢＲＣＡ１,ＢＲＣＡ２基因定位和克隆后,近年来对上述基因相关家族的特点,基因外显率,抑癌机制,基因突变热点,突变类型的种族特异性等方面的研究进展,介绍了肿瘤高度和中度危险家族的划分方法和意义,并分析了今后我国在相关领域深入研究的思路。     

中国上海家族性乳腺癌BRCA1和BRCA2基因的突变

目的研究上海地区家族性乳腺癌中BRCA1／BRCA2基因的突变位点及携带情况。方法研究对象来自35个汉族家族性乳腺癌家系，家系中至少有一个一级亲属乳腺癌患病史。共35例患者，其中13例发病年龄≤加岁。由静脉血提取基因组DNA，对BRCA1／BRCA2基因的全部编码序列进行扩增。扩增产物突变分析先由变性高效液相色谱分析进行筛查，之后进行DNA直接测序证实。结果在BRCA1基因中发现有4个突变位点，其中2个为新发现位点——拼接点突变（IVS17-1G〉T；IVS21＋1G〉C）；另两个为已报道的致病突变位点——移码突变（1100delAT；5640delA）。BRCA2基因的1个致病突变位点位于11号外显子上，为移码突变（5802delAATT）。另外，共发现有12个新的单核苷重复多态位点，都未引起氨基酸编码改变；其中，8个在BRCA1基因上，4个在BRCA2基因上。在家族性乳腺癌中，BRCA1突变频率（11．4％）高于BRCA2基因（2．9％）。结论新发现的2个BRCA1基因的拼接点突变可能是中国上海人群家族性乳腺癌的特有突变位点；在我国上海地区人群中，BRCA1基因突变起着比BRCA2基因更大的作用；该研究丰富了中国人群中BRCA基因的突变谱，并为未来的临床基因检测提供了筛查模式。     

Systematic misclassification of missense variants in BRCA1 and BRCA2 “coldspots”

PurposeGuidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use “coldspots,” that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots.MethodsWe used Bayesian approaches to model variant classification in these regions.ResultsBRCA1 exon 11 (~60% of the coding sequence), and BRCA2 exons 10 and 11 (~65% of the coding sequence), are coldspots. Of 89 pathogenic (P) or likely pathogenic (LP) missense variants in BRCA1, none are in exon 11 (odds <0.01, 95% confidence interval [CI] 0.0–0.01). Of 34 P or LP missense variants in BRCA2, none are in exons 10–11 (odds <0.01, 95% CI 0.0–0.01). More than half of reported missense variants of uncertain significance (VUS) in BRCA1 and BRCA2 are in coldspots (3115/5301 = 58.8%). Reclassifying these 3115 VUS as likely benign would substantially improve variant classification.ConclusionIn BRCA1 and BRCA2 coldspots, missense variants are very unlikely to be pathogenic. Classification schemes that incorporate coldspots can reduce the number of VUS and mitigate risks from reporting benign variation as VUS.     

BRCA1基因复杂甲基化模式

应用体外甲基化酶M-SssI处理和甲基化敏感单链构象分析法(Methylation-sensitive single-strand conformation     

散发性乳腺癌中BRCA1基因突变

为探讨散发性乳腺癌发生的分子机理与ＢＲＣＡ１基因异常的关系，应用聚合酶链反应（ＰＣＲ）结合单链构象多态性分析（ＳＳＣＰ）和核酸序列分析方法，研究了２０例散发性乳腺癌组织和６例正常人外周血样品中ＢＲＣＡ１基因外显子５、１１区域的突变情况。结果显示：２０例散发性乳腺癌组织中，２例在外显子１１（ｎｔ３５５２－ｎｔ３８０４区域）发生突变；１例在ｎｔ３６６７发生Ａ→Ｇ点突变；另一例在该区域上发生约３５０ｂｐ的大片段插入突变。表明编码区基因突变引起的ＢＲＣＡ１失活可能至少与少部分散发性乳腺癌的发生有关，同时也证实了ＢＲＣＡ１基因对乳腺癌的肿瘤抑制功能，为乳腺癌的病因学研究提供了有用的资料。     

肿瘤易感基因BRCA1

BRCA1为一新的肿瘤易感基因,定位在17q21,其cDNA可转录7.8kb mRNA,编码含1863个氨基酸残基的长多肽,在遗传性乳腺卵巢癌中有高频率的BRCA1基因杂合性丢失,同时有多形式多位点的基因突变,符合肿瘤抑制基因特点。     

乳腺癌易感基因BRCA2

ＢＲＣＡ２为一新研究发现的遗传性乳腺癌的第二个易感基因，定位在１３ｑ１２－１３，可转录７．３ｋｂ ｍＲＮＡ，编码含２３３９个氨基酸残基的长多肽，有多形式多位点的基因突变，导致其编码蛋白质生物活性的丧失。     

肝细胞癌中BRCA2基因突变

研究证实肝细胞癌（HCC）杂合性缺失和胰腺癌（PC）频繁的等位基因缺失涉及染色体13q．缺失图谱分析分离出HCC中该染色体臂上常见的两个缺失区。域．一是含有RB1座位的14q，另一区域与14q相邻．Zhang等报道HCC中罕见RB基因体细胞突变．提示这种肿瘤涉及另外一肿瘤抑制基因。最近从染色体13q上邻近RB座位的一个区域中分离出乳腺癌身感基因BRCA2．胰腺癌细胞株BRCA2区域纯合性缺失已有报道．因此作者对涉及HCC和PC发生的BRCA2基因进行了检测．使用PCR－SSCP和多重PCR－SSCP技术对60例HCC和36例PC中分离的DNA的BRCA2…     

BRCA1的生物学特性研究进展

本文综述了乳腺癌易感基因BRCA1生物学特性研究进展。在阐明BRCA1基因结构特点的基础上,着重介绍了它作为一种新的肿瘤抑制基因在细胞生长发育、核转录调控及DNA损伤修复中的作用。     

BRCA基因突变检测的标准化研究

目的 使用BRCA基因突变国家参考品,评价BRCA1/2基因突变检测试剂盒(联合探针锚定聚合测序法)的性能.方法 取国家参考品的基因组DNA,进行打断和末端修复,获得片段化的DNA.使用连接酶在DNA两端加上接头.经pre-PCR扩增获得杂交前文库(pre-PCR文库),再用探针特异性捕获含目标区域的DNA片段,经po...     

Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks?

Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy).We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC.Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.     

三阴性乳腺癌患者BRCA1和BRCA2基因突变的临床特征及预后因素

目的:探究三阴性乳腺癌患者BRCA1和BRCA2基因突变检测的临床意义及预后因素分析.方法:研究对象选取为2003年1月至2015年12月之间的三阴性乳腺癌156例,所有患者均通过PCR法和DNA序列测定检验BRCA1和BRCA2基因突变情况,分析乳腺癌患者BRCA1和BRCA2基因突变特点.应用Log-Rank检验对BRCA1和/或BRCA2基因突变的三阴性乳腺癌患者的各项指标如年龄、ECOG状态、临床分期、淋巴结阳性数、月经状态和给药方式进行单因素分析.应用Cox风险比例回归模型分析患者年龄、ECOG状态、临床分期、淋巴结阳性数、肿瘤大小、月经状态和给药方式等多因素分析.结果:三阴乳腺癌患者发生基因突变21例,总体发生率13.46％,BRCA1突变15例,BRCA2突变6例.Log-Rank检验结果显示,发病年龄越大,ECOG评分越高,临床分期越晚,淋巴结阳性数越多,预后越差(P＜0.05),而发病时月经状态和给药方式与预后无关.COX风险比例回归模型显示,肿瘤大小(相对危险度,3.163;95％CI:1.455～9.287;P＜0.05)和淋巴结转移数(相对危险度,1.859;95％CI:1.254～6.875;P＜0.05)是BRCA基因突变三阴性乳腺癌独立的预后因素.结论:BRCA1和BRCA2基因突变可能与乳腺癌尤其是三阴乳腺癌可能有着密切的相关性,发病年龄、ECOG评分,临床分期和淋巴结阳性数及肿瘤大小与BRCA基因突变的三阴乳腺癌预后有关.     

乳腺癌相关基因BRCA1和BRCA2专利案引发的基因可专利性思考

<正>基因发明的可专利性多年来一直备受争议,其在一些主要国家均能获专利保护,然而,美国最高法院于2013年对Myriad案的判决改变了美国对于基因可专利这个议题的态度,并进一步影响了美国专利商标局(USPTO)的相关专利的审查标准,本文通过回顾和分析Myriad案始末,探讨该案对美国基因专利领域的深远影响,以期对我国拟进军美国相关市场的专利申请人提出建议。     

新疆地区维吾尔族乳腺癌BRCA1基因突变分析

目的研究新疆地区维吾尔族乳腺癌患者BRCA1基因突变情况及突变位置。方法选取70例维吾尔族乳腺癌根治标本,对照组为32例维汉族乳腺良性病变（纤维腺病及纤维腺瘤）及乳腺癌旁非癌组织;应用PCR-单链构象多态性和DNA序列测定的方法检测BRCA1基因突变。结果（1）70例维吾尔族乳腺癌中发现9例BRCA1突变的12个新位点。（2）70例维吾尔族乳腺癌BRCA1的突变率为12.86%（9/70）,22例维吾尔族早发性乳腺癌（≤35岁）BRCA1突变率为31.82%（7/22）。维吾尔族早发性乳腺癌BRCA1突变率（7/22）高于维吾尔族晚发性乳腺癌（2/48）,差异有统计学意义（χ^2=10.295,P〈0.01）。（3）70例维吾尔族乳腺癌中发现9例BRCA1基因核苷酸多态性位点,其中8例多态性位点均为3232A〉G。（4）2例双侧乳腺癌中均检测出BRCA1基因的突变。结论BRCA1突变可能与新疆维吾尔族乳腺癌尤其是维吾尔族早发性乳腺癌及双侧乳腺癌的发生密切相关。     

BRCA1基因启动子复杂甲基化模式

应用体外甲基化酶M－SssI处理和甲基化敏感单链构象分析法（Methylation-Sensitive single-strand ccnformation analysis,MS-SSCA)及DNA测序技术，研究正常人乳腺癌易感基因1（breast cancer1,BRCA1)启动子区5’端CpG岛13个CG二核苷酸位点的甲基化模式。对甲基化酶处理时间不同得到的8种有差异MS0SSCA迁移带型进行测序，证实为8种不同的甲基化模式，结果将为研究临床乳腺癌标本BRCA1基因甲基化模式提供参考。     

Informed consent documents for BRCA1 and BRCA2 screening: how large is the readability gap?

The decision to undergo testing for the BRCA1 and BRCA2 mutations, which are associated with an increased risk of breast and ovarian cancer, can have long-term consequences on women's lives. Women who decide to undergo such testing are required to sign informed consent documents, which indicate that they understand the test and its risks and benefits. These documents are generally written for advanced-level readers. However, the reading abilities of many women are substantially lower than the level of the consent forms, resulting in a 'readability gap'. This disparity suggests that women may not fully understand the documents they are asked to sign. The 'readability gap' poses the serious issues about informed consent, raising questions about institutional review boards and the effectiveness of the documents that are currently in use.     

散发性乳腺癌BRCA1基因甲基化的研究

目的 研究散发性乳腺癌中BRCA1基因启动子区域的异常甲基化特性。方法 采用甲基化敏感的限制酶（methylation-sensitive restriction endonucleases,MSRES)法。结果 在34例散发性乳腺癌中有6例乳腺癌患者的BRCA1基因启动子区域出现了异常甲基化现象。结论 BRCA1基因的异常甲基化发生率较高，筛查BRCA1基因的异常甲基化对于乳腺癌患病风险评估、早期诊断及治疗具有重要的临床意义。     

中国福建遗传性乳腺癌BRCA1基因突变分析

目的研究福建遗传性乳腺癌患者BRCA1基因突变位点及携带情况。方法对20例遗传性乳腺癌患者血液标本进行检测,对其BRCA1基因第11号外显子全序列进行DNA测序。结果20例标本中检出5患者存在共计9种BRCA1基因突变,其中3个为新发现位点（错义突变1159T〉C,4071A〉C;同义突变4122C〉T）;其它6个已报道位点中2个（2201C〉T,2430T〉C）为同义突变,其余4个（2685T〉C,2731C〉T,3232A〉G,3667A〉G）属错义突变,本研究中BRCA1突变率为25%。结论福建遗传性乳腺癌患者BRCA1基因突变具有地域性特征,开展BRCA1基因突变检测有助于本地区女性患癌风险评估和早期诊断。