353例遗传性高危乳腺癌患者BRCA1、BRCA2、PALB2基因胚系突变的分布情况研究

[目的]通过对女性乳腺癌患者进行胚系基因检测,评估BRCA1、BRCA2、PALB2基因胚系致病/可能致病性突变在高危乳腺癌患者中的分布情况。[方法]收集2016年12月1日至2022年4月30日中山大学附属第一医院收治的女性乳腺癌患者,对已进行胚系多基因检测的353例具有遗传性高危因素的女性乳腺癌患者,对她们的检测结果进行分析,评估BRCA1、BRCA2和PALB2基因胚系致病/可能致病性突变患者的病理和临床特征等情况。[结果] 353例患者中,胚系BRCA1、BRCA2和PALB2致病/可能致病突变者共59例,突变率为16.71%,年轻患者较其他年龄患者的BRCA1突变率更高（P=0.039）,相比其他分子分型,三阴性乳腺癌患者的BRCA1突变（P<0.001）和3个基因的总突变率（P=0.007）都明显更高。和没有肿瘤家族史的患者相比,有肿瘤家族史的患者并没有体现出明显的高突变率。具有2个或2个以上危险因素的患者的基因突变率要明显高于只有1个高危因素的患者（P=0.048）。[结论] PALB2基因胚系致病/可能致病突变在高危乳腺癌患者中的发生比例较高,其重要性并不亚于BR...     

BRCA1/2突变乳腺癌临床诊治新进展—机遇和挑战

BRCA1/2胚系突乳腺癌具有特殊的发病机制及临床病理特征,其临床决策有别于散发性乳腺癌。随着基因测序技术的发展,越来越多的BRCA1/2突变乳腺癌被检测出。BRCA1/2突变乳腺癌的相关临床管理越来越得到重视。本文总结近年来的相关文献,对BRCA1/2突变乳腺癌患者的基因检测和手术、化疗、靶向治疗等诊疗进展进行综述,以期为BRCA1/2突变患者的临床决策提供帮助。      

68例中国新疆多民族地区遗传性乳腺癌患者BRCA1和BRCA2突变研究

  目的  分析中国新疆多民族地区的高风险遗传性乳腺癌BRCA1/2基因突变位点情况。  方法  以2009年1月到2010年12月新疆医科大学附属肿瘤医院收治的来自新疆地区的68例符合高风险遗传性乳腺癌标准的患者为研究对象,其中HBC 12例,HBOC 4例,E-BC 25例,BI-BC 10例,TNB 17例。通过外周静脉血提取基因组DNA,对BRCA1/2基因的全部编码序列进行扩增。用高效液相色谱分析（DHPLC）进行突变分析预筛,结果经DNA测序验证。  结果  BRCA1/2致病性突变在新疆地区高风险遗传性乳腺癌的突变率为8.8%（6/68）。其中BRCA1的突变率为4.4%（3/68）,BRCA2的突变率为4.4%（3/68）。不同民族之间BRCA1/2突变率无统计学差异。  结论  中国新疆多民族地区的高风险遗传性乳腺癌患者部分病例具有与内地汉族人群不同的BRCA基因突变谱。BRCA1 2073delA,BRCA2 6873del CTCC及BRCA2 9481del A可能是新疆遗传性乳腺癌特有的突变位点。      

100例遗传性乳腺癌胚系基因BRCA1/2突变研究

目的探讨遗传性乳腺癌患者胚系基因BRCA1/2的外显子区域突变情况及其与临床病理特征的关系。 方法本研究为回顾性研究。根据纳入和排除标准,选择2014年2月至2016年2月山西省人民医院乳腺外科确诊的100例遗传性乳腺癌患者作为研究对象,采用二代测序技术检测患者胚系基因BRCA1/2突变的情况,并收集其年龄、组织学分级、淋巴结状态以及ER、PR、HER-2状态等临床病理资料。然后,采用Fisher确切概率检验比较BRCA1与BRCA2基因突变类型的差异,并用χ²检验分析BRCA1/2基因突变与乳腺癌患者临床病理特征的关系。 结果在100例遗传性乳腺癌患者中,有6例患者携带BRCA1基因突变,11例患者携带BRCA2基因突变。而在6例BRCA1基因突变者中,发生移码突变和无义突变者分别占4/6、2/6;在11例BRCA2基因突变者中,发生移码突变和无义突变者分别占4/11、7/11;2组间比较,基因突变类型的差异无统计学意义(P＝0.335)。在组织学分级1、2级的患者中,携带BRCA1、BRCA2基因突变者以及不携带BRCA1/2基因突变者分别占4.4%(4/91)、8.8%(8/91)和86.8%(79/91),而在组织学分级为3级的患者中,携带BRCA1、BRCA2基因突变者及不携带BRCA1/2基因突变者分别占2/9、3/9和4/9,组间比较,差异有统计学意义(χ²＝9.398,P＝0.007)。在HER-2阴性乳腺癌患者中,携带BRCA1、BRCA2基因突变者及不携带BRCA1/2基因突变者分别占10.7%(6/56)、16.1%(9/56)和73.2%(41/56),而在HER-2阳性乳腺癌患者中,携带BRCA1、BRCA2基因突变者及不携带BRCA1/2基因突变者分别占0(0/44)、4.5%(2/44)和95.5%(42/44),组间比较,差异有统计学意义(χ²＝9.072,P＝0.007)。 结论遗传性乳腺癌患者胚系基因BRCA1/2突变在不同组织学分级、不同HER-2状态的患者间存在差异。本研究在丰富遗传性乳腺癌临床遗传学资料的同时,可能为后期的个体化精准治疗奠定一定的理论依据。     

乳腺癌BRCA1/2基因大片段重排的研究进展北大核心CSCD

乳腺癌是女性最常见的恶性肿瘤,BRCA1与BRCA2是乳腺癌最重要的易感基因,携带BRCA1/2胚系突变的女性,其乳腺癌的终身患病风险显著增高。BRCA1/2致病性突变多为单个或数个碱基改变引起的移码突变和无义突变,但常规的Sanger测序筛查方法尚不足以发现BRCA1/2其他胚系缺陷类型,如大片段重排。随着基因检测方法的进步,多种BRCA1/2基因重排被发现,在遗传性乳腺癌家族接受常规BRCA1/2基因测序未发现突变的情况下,应认真考虑检测大片段重排,以免漏诊。     

中国BRCA1/2突变阳性和突变阴性乳腺癌病理学特征的比较性研究

背景与目的：BRCA1和BRCA2是两个最主要的遗传性乳腺癌相关基因,本研究旨在发现中国BRCA1/2突变阳性乳腺癌的病理学特征。方法：本研究入组了2012—2016年间287例接受过BRCA1/2基因突变检测的乳腺癌,对其中BRCA1/2突变阳性和突变阴性患者的组织病理学和免疫组织化学检测结果进行了比较性研究。结果：在287例乳腺癌中,66例为BRCA1突变阳性,47例为BRCA2突变阳性,174例为BRCA1/2突变阴性。BRCA1突变的乳腺癌表现为更高的组织学分级（P＜0.001）,更高比例的三阴性乳腺癌（72.7%,P＜0.001）。BRCA1突变阳性和BRCA2突变阳性的乳腺癌中人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）的阳性表达率较BRCA1/2突变阴性的乳腺癌更低（P＜0.001）。BRCA1突变阳性乳腺癌基底标志物细胞角蛋白5/6（cytokeratin 5/6,CK5/6）和表皮生长因子受体（epidermal growth factor receptor,EGFR）的阳性率为50%,明显高于其他两组（P＜0.001）,雄激素受体（androgen receptor,AR）的阳性率也更低（P＜0.05）。结论：中国BRCA1突变阳性乳腺癌更多为三阴性乳腺癌,具有CK5/6和EGFR的阳性率更高等特点,并且BRCA1和BRCA2突变阳性乳腺癌中HER2受体阳性率也更低。     

BRCA1/2胚系突变对三阴性乳腺癌患者放疗后第二原发肿瘤的影响

背景与目的：乳腺癌易感基因1/2(BRCA1/2)的编码产物在维持机体基因组稳定性方面发挥着重要的作用。BRCA1/2致病突变是否会导致机体对放射线的脆弱度增加,从而诱发第二原发肿瘤尚不清楚。本文旨在探讨BRCA1/2基因胚系突变的三阴性乳腺癌患者术后接受放射治疗是否是增加罹患第二原发肿瘤的危险因素。方法：基于复旦大学附属肿瘤医院2007年1月1日—2014年12月31日收集的回顾性三阴性乳腺癌队列（292例为BRCA1/2突变的女性三阴性乳腺癌患者）,针对其开展分析,分别在非BRCA1/2胚系突变患者（n=261）与BRCA1/2胚系突变患者（n=31）中进行多元logistic回归分析,以评估影响第二原发肿瘤的风险因素,并对上述两人群中的分析结果进行交互作用分析,从而评估BRCA1/2胚系突变与放疗的交互作用。本研究除特殊说明外,均采用双侧检验且检验水准α=0.05。本研究所有样本的获得与使用均得到了复旦大学附属肿瘤医院伦理委员会的批准（050432-4-2108）,且每个患者均提供了书面知情同意。结果：在BRCA1/2胚系突变患者中进行多元logistic回归分析提示术后接受放疗...     

BRCA1/2基因检测在恶性肿瘤中的应用

乳腺癌易感基因BRCA1/2（breast cancer gene 1/2）在细胞DNA损伤和修复通路中发挥着关键作用，对于保持基因组的完整性至关重要。早期研究发现BRCA1/2是遗传性乳腺癌/卵巢癌综合征的主要致病因素，BRCA1/2突变携带者罹患乳腺癌和卵巢癌的风险大幅增加；近年研究表明，BRCA1/2突变增加了结肠癌、胰腺癌、皮肤癌以及男性前列腺癌等的发病风险。BRCA1/2突变患者存在共同的分子病理基础，将来可能独立于病理组织诊断之外，作为临床药物治疗的重要依据，包括铂类为代表的化疗药、PARP抑制剂、PD-1抗体、ALDH2抑制剂、mTOR抑制剂等。      

新疆维吾尔自治区高风险三阴性乳腺癌30例BRCA基因突变及临床病理特征对比

目的 了解新疆维吾尔自治区高风险三阴性乳腺癌（TNBC）BRCA基因突变情况及BRCA基因突变者与未突变者临床病理特征的差异.方法 以新疆维吾尔自治区30例符合高风险TNBC标准的患者为研究对象,抽取外周静脉血,提取基因组DNA,对BRCA1/2基因的全部编码序列进行扩增.变性高效液相色谱分析（DHPLC）预筛BRCA1/2基因突变,经DNA测序证实.对比分析BRCA突变者与未突变者的临床病理特征.结果 30例患者中,5例（16.7％）BRCA基因发生致病性突变,其中BRCA1突变4例（13.3％）,BRCA2突变1例（3.3％）;25例（83.3％）未发现BRCA基因突变.突变者与未突变者相比,临床病理分期早,差异有统计学意义（P=0.040）.结论 新疆维吾尔自治区高风险TNBC BRCA1基因突变率高,对于高风险TNBC患者建议进行BRCA基因检测;高风险TNBC BRCA基因突变者与未突变者相比,可能在临床病理特征方面存在差异,应考虑个体化治疗.     

中国前列腺癌患者BRCA1/2及ATM基因的胚系突变研究

背景与目的：BRCA1/2、ATM基因的致病性胚系突变与前列腺癌的发病风险和疾病进展密切相关,同时可对转移性去势抵抗性前列腺癌（metastatic castration-resistant prostate cancer,mCRPC）患者的PARP抑制剂治疗、铂类化疗进行指导,然而,基于中国人群的研究鲜有报道。本研究旨在揭示中国人群前列腺癌患者BRCA1/2、ATM基因的胚系突变率,从而指导基因检测和临床治疗。方法：前瞻性分析53例遗传咨询门诊确诊为前列腺癌患者的临床资料,并对这些患者的胚系DNA进行测序,将目标基因BRCA1/2、ATM的突变依据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics,ACMG）遗传突变分类标准与指南评估致病性。同时对致病性突变与前列腺癌患者发病年龄、家族史、Gleason评分、前列腺特异抗原（prostate-specific antigen,PSA）值、肿瘤转移之间的关系进行统计学分析。结果：中国人群前列腺癌患者BRCA1/2、ATM基因的致病性胚系突变率为7.55%,转移性前列腺癌患者的突变率为9.68%。在中国人群中,BRCA1/2、ATM基因的致病性突变与前列腺癌的早期发生有关（P=0.011）;但在家族史、Gleason评分、PSA水平及肿瘤转移上差异无统计学意义（P>0.05）。结论：本研究初步建立了中国人群基因检测推荐标准,对包括转移性前列腺癌患者和早发前列腺癌患者在内的高危胚系突变者推荐进行基因筛查,以更好地进行临床诊疗及遗传咨询。     

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2–4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4–88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.     

Prevalence and characterization of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutations in Chinese women with familial breast cancer

Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing.     

Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2

Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person-years). Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13–2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57–9.19). There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population-based guidelines for breast cancer screening.     

中国汉族BRCA1/2突变的乳腺癌家系中其他肿瘤发病风险分析

目的 研究携带BRCA1/2突变的中国汉族家族性乳腺癌家系中非乳腺癌和卵巢癌的其他肿瘤发病风险.方法 采用聚合酶链反应(PCR)-直接测序法检测465个汉族家族性乳腺癌家系中先证者的BRCA1/2基因胚系突变,比较突变组与非突变组有非乳腺癌和卵巢癌的其他肿瘤家族史的比例.结果 在465例汉族家族性乳腺癌先证者中,BRCA1/2突变者47例(10.1％),非突变者418例(89.9％).在BRCA1/2突变组和非突变组中,两者总的非乳腺癌和卵巢癌的其他肿瘤家族史比例差异无统计学意义(突变组与非突变组,27.7％∶29.9％,x2=0.10,P=0.75);但两组的瘤谱分布有差别,在突变组的家族中最常见肿瘤为胃癌、胰腺癌和前列腺癌;而在非突变组家族中最常见的为肺癌、胃癌和食管癌.进一步分析发现胃癌、胰腺癌和前列腺癌3种肿瘤家族史总的比例在突变组中显著高于非突变组(突变组与非突变组,17％∶7.7％,Fisher精确概率法P=0.048).突变组家族中发生胃癌、胰腺癌和前列腺癌的风险为非突变组家族的2.47倍(95％ CI为1.07 ～ 5.74).结论 在中国汉族家族性乳腺癌患者中,相比较于非BRCA1/2突变家系,BRCA1/2突变患者的家系有相对较高的风险发生胃癌、胰腺癌和前列腺癌.     

BRCA1/2突变的中国健康女性乳腺预防性切除及Ⅰ期重建的临床实践

目的:探讨对携带BRCA1/2突变的中国健康女性实施乳腺预防性切除及I期重建的可行性。方法:选择2018年1月至2019年2月3例于北京大学国际医院就诊的携带BRCA1/2突变的中国健康女性,其中2例携带BRCA1突变、1例携带BRCA2突变,均有乳腺癌家族史,年龄为34~36岁,实施预防性保留乳头-乳晕的双侧乳腺切除和Ⅰ期假体重建术。结果:3例患者术后无并发症发生,术后中位随访时间为18个月,均无乳腺癌发生,对重建乳房外形满意,且焦虑和恐惧情绪显著下降,取得良好的疗效。结论:对携带BRCA1/2突变且有乳腺癌家族史的中国健康女性,在严格筛选的基础上,可慎重开展乳腺预防性切除及Ⅰ期重建术。     

Breast cancer risk among male BRCA1 and BRCA2 mutation carriers

Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).     

Genetic epidemiology of BRCA1 mutations in Norway

Familial breast-ovarian cancer has been demonstrated to be frequent but unevenly distributed in Norway. This was assumed to be caused by the reduced population size created by the medieval Bubonic plagues 25 generations ago, and by the following rapid expansion. We have previously reported that four mutations account for 68% of the BRCA1 mutation carriers. Subsequent analysis has resulted in a total of 100 separate families carrying one of these founder mutations. The four mutations occurred on one specific BRCA1 haplotype each. The 1675delA, 816delGT and 3347delAG families originated from the South-West coast of Norway with a few families in the north, while the traceable ancestors of the 1135insA families clustered along the historical inland road from the South-East to mid-Norway. The carriers of each of the four mutations today are descendants of one or a few individuals surviving the plagues. We may identify the majority of BRCA1 mutation carriers in Norway by screening for local founder mutations.     

Comparative disease pattern of a patient with a novel BRCA2 truncation and knockout models for BRCA2

We report a novel germline 490delCT mutation in BRCA2 gene, detected in a 38-year-old woman with breast cancer. The mutation originates a premature stop at codon 99, leading to a truncated protein, and has not been documented in any published report to the best of our knowledge.     

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment

Background

The prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.

Methods

Two retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.

Results

Genotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).

Conclusion

BRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.     

Aromatase expression is increased in BRCA1 mutation carriers

Background  

Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls.