乳腺癌BRCA1基因研究进展

BRCA1（breast cancer susceptibility gene 1）是研究得比较深入的乳腺癌易感基因，其在家族性乳腺癌中的高突变率一直吸引着国内外学者对其引发乳腺癌的机制进行探索。而近年来，在散发性乳腺癌中，BRCA1启动子的高甲基化现象更使其成为了研究的热点。本文将对BRCA1的结构与功能、遗传背景及其未来应用的展望这三部分进行综述。并重点介绍BRCA1启动子甲基化与乳腺癌的关系，以及近年来对BRCA1启动子甲基化的研究进展。     

BRCA1表达与Ⅲ期胃腺癌患者术后特异性生存的关系

目的:探索乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)在Ⅲ期胃腺癌中表达及其与患者特异性生存的关系.方法:采用免疫组化EnVision二步法检测300例Ⅲ期胃癌组织中BRCA1蛋白的表达情况,并分析其与预后的关系.结果:胃癌组织中BRCA1蛋白阳性表达率为32....     

中国汉族家族性及早发性乳腺癌患者BRCA2启动子突变情况的研究

乳腺癌是女性最常见的恶性肿瘤之一.除性别、年龄外,有肿瘤家族史也是乳腺癌发病的1个高危因素.在有乳腺癌家族史的患者中通常都能发现易感基因的突变.目前已发现多个与乳腺癌发病相关的易感基因(breast cancer susceptibility gene,BRCA),而其中BRCA1及BRCA2则是最主要的两个基因 [1-2].     

ERCC1、BRCA1在非小细胞肺癌的表达与顺铂耐药的研究进展

顺铂广泛应用于非小细胞肺癌（non—small cell lung cancer,NSCLC）的化疗,但耐药性的产生严重影响其疗效。顺铂耐药的机制尚不十分清楚。目前普遍认为错配切除修复蛋白1（excision repair croess completion gene1,ERCC1）及乳腺癌易感基因1（breast cancer susceptibility gene1,BRCA1）的表达与顺铂耐药性相关。抑制ERCC1及BRCA1的表达可克服顺铂耐药性,提高治疗效果。     

38例散发乳腺癌患者BRCA1基因突变检测

肿瘤易感基因BRCA1(breast and ovarian canoer suscepti-bility gene,BRCA1)与乳腺癌,卵巢癌发生有密切联系,它的失活可导致细胞的恶性转化和肿瘤的发生.BRCA1基因突变者患癌的风险远高于普通群体,对于有家族史的高危人群中筛查BRCA1基因,对于乳腺癌卵巢癌患者风险评估,发病检测,早期诊断及今后的基因治疗等都有很重要的临床意义.     

186例乳腺癌患者BRCA1基因突变检测

目的 分析186例散发乳腺癌患者肿瘤易感基因BRCA1（breast and orarian cancer susceptibility gene,BRCA1)突变情况及突变位置。方法 应用PCR－SSCP（single-stranded canformational polymorphs,SSCP)和直接测序方法定位,检测乳腺癌部分患者部分BRCA1基因外显子和内含子与外显子之间接拼区突变及突变位置。结果 186例患者中,有13例发生BRCA1基因突变,突变例数占总例数的7．0％,其中8例突变位置在内含子与外显子的拼接区,5例突变位置在外显子上。结论 筛查BRCA1基因突变对于乳腺癌患病风险评估、发病检测、早期诊断及基因治疗具有重要的临床意义。     

BRCA1基因的功能及其上游调控序列结构功能特征

乳腺癌易感基因1(BRCA1)是一种与家族性乳腺癌、家族性卵巢癌密切相关的抑癌基因.但其在散发性乳腺癌中尚未见突变的报道,而在散发性乳腺癌中其表达下降,说明其转录调控异常可能参与散发性乳腺癌的发生.本文拟对BRCA1功能及上游调控区结构功能特征作一综述.     

荧光定量聚合酶链反应检测BRCA1和BRCA2 mRNA表达在散在乳腺癌诊断中的应用

目的:荧光定量聚合酶链反应(FQ-PCR)技术检测乳腺癌易感基因1（breast cancer susceptibility gene 1,BRCA1）、乳腺癌易感基因2的表达及其与临床病理特征之间的关系,探讨其在散在乳腺癌诊断中的应用。方法:采用FQ-PCR法,并以甘油醛-3-磷酸脱氢酶（GAPDH）为内对照测定30名健康女性体检者、55例良性乳腺疾病患者、96例乳腺癌患者外周血中BRCA1和BRCA2的表达量。结果:乳腺癌患者BRCA1和BRCA2的mRNA显著低于健康女性体检者和良性乳腺疾病患者。健康女性体检者和良性乳腺疾病患者BRCA1和BRCA2的mRNA无显著性差异。GAPDH和BRCA1/BRCA2比值在三组间无显著性差异。乳腺癌BRCA2 mRNA显著高于BRCA1。BRCA1和BRCA2 mRNA之间有微弱的相关性（r=0.378,P<0.01）。BRCA2 mRNA和BRCA1/BRCA2比值与临床病理（ER和PR、组织学分级）存在相关性。BRCA1基因表达与临床病理不存在相关性。结论:采用FQ-PCR检测BRCA1和BRCA2基因表达水平,可有效监测散在乳腺癌的诊断、疗效和转移。     

ERCC1 、BRCA1在非小细胞肺癌的表达与顺铂耐药的研究进展

顺铂广泛应用于非小细胞癌(non-small cell lung cancer,NSCIC)的化疗,但耐药性的产生严重影响其疗效.顺铂耐药的机制尚不十分清楚.目前普遍认为错配切除修复蛋白1(excision repair cross completion gene 1,ERCC1)及乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)的表达与顺铂耐药性相关.抑制ERCC1及BRCA1的表达可克服顺铂耐药性,提高治疗效果.     

乳腺癌易感基因1／2的研究进展

乳腺癌易感基因（breast cancer susceptibility gene,BRCA）1是世界上第一个被发现的家族性乳腺癌抑癌基因。BRCAl分离出1年以后,研究者又鉴定和克隆出第二个乳腺癌抑癌基因BRCA2[1-2]。     

The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers

BACKGROUND:

We assessed the efficacy of taxane chemotherapy in BRCA1‐ and BRCA2‐associated patients compared with sporadic metastatic breast cancer patients.

METHODS:

Response rates (RRs) to and progression‐free survival (PFS) after taxane chemotherapy of 35 BRCA1‐associated and 13 BRCA2‐associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third).

RESULTS:

Among BRCA1‐associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)‐negative patients, BRCA1‐associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec‐positive patients were similar in BRCA1‐associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2‐associated patients, who were mainly HRec‐positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively).

CONCLUSIONS:

BRCA1‐associated, HRec‐negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec‐negative patients. HRec‐positive BRCA1‐ and BRCA2‐associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients. Cancer 2012;. © 2011 American Cancer Society.     

乳腺癌组织中乳腺癌易感基因1、增殖细胞核抗原Ki-67表达的临床意义

目的 探讨乳腺癌组织中乳腺癌易感基因1（BRCA1）、增殖细胞核抗原Ki-67表达的临床意义.方法 采用免疫组织化学法检测194例乳腺癌病理组织标本BRCA1、Ki-67的表达情况,并对其与临床病理参数的相关性进行分析.结果 194例乳腺癌中,淋巴结阳性组、雌激素受体（ER）/孕激素受体（PR）阴性组和人表皮生长因子受体2（HER-2）阳性组的BRCA1低表达率较高（P＜0.05）,三阴组中BRCA1低表达率高于非三阴组（P＜0.05）;Ki-67高表达者多为组织分级较高、ER/PR阴性和HER-2阳性患者（P＜0.05）;且BRCA1和Ki-67具有负相关性（P＜0.05）,绝经后、组织分级低、淋巴结阳性、ER/PR阴性、HER-2阳性患者的BRCA1低表达合并Ki-67高表达所占比例较高（P＜0.05）,但在三阴组与非三阴组间差异无统计学意义.结论 联合检测BRCA1、Ki-67对乳腺癌的临床转归具有一定预测意义,尤其是BRCA1可作为三阴性乳腺癌的预后因素之一.     

乳腺癌BRCA1基因突变及其蛋白表达研究

目的 :探讨散发性乳腺癌的BRCA1基因突变及其蛋白表达与临床病理因素的关系。方法 :收集乳腺癌患者外周血 10 2份、新鲜肿瘤组织 30份 ,分别采用PCR SSCP、DHPLC和基因测序对BRCA1基因第 2、8- 1、8- 2和 2 0外显子进行突变检测 ;对 10 4例肿瘤组织切片进行免疫组化染色标记BRCA1蛋白表达 ,分析免疫组化结果与临床资料的关系。结果 :分别在外显子 8- 1和 8- 2的 2 882 1和 2 8978位点上发现 3例碱基缺失和置换现象。BRCA1蛋白在乳腺癌组织中表达下降 ,且与患者生存状态有关。结论 :在中国散发性乳腺癌患者中BRCA1基因外显子 2、8和 2 0的突变率较低 (2 3% ) ,可以认为在普通中国人群中乳腺癌的发生与该部分碱基序列突变的关系不大 ,但BRCA1蛋白低表达乳腺癌患者复发的危险性增大     

BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC(50) : 30-40 microM) compared with MCF-7 (IC(50) : 60-70 microM) and MDA-MB231 (IC(50) : 90-100 microM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC(50) : 45-50 microM) compared with MCF-7 (IC(50) : 1-5 microM) and MDA-MB231 (IC(50) : 5-10 microM) (P<0.02), as well as to paclitaxel (Tax) (IC(50) : >2 microM for HCC1937, 0.1-0.2 microM for MCF-7 and 0.01-0.02 microM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.     

Autoimmune response to PARP and BRCA1/BRCA2 in cancer

Purpose

To determine the role of autoantibodies to PARP1 and BRCA1/BRCA2 which were involved in the synthetic lethal interaction in cancer.

Methods

Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect autoantibodies to PARP1 and BRCA1/BRCA2 in 618 serum samples including 131 from breast cancer, 94 from lung cancer, 34 from ovarian cancer, 107 from prostate cancer, 76 from liver cancer, 41 from pancreatic cancer and 135 from normal individuals. The positive sera with ELISA were confirmed by Western blot. Immunohistochemistry was used to examine the expression of PARP1 and BRCA1/BRCA2 in breast cancer.

Results

Autoantibody frequency to PARP1, BRCA1, and BRCA2 in cancer varied from 0% to 50%. When the sera from cancer patients were tested for the presence of autoantibodies to PARP1 and BRCA1/BRCA2, the autoantibody responses slightly decreased and the positive autoantibody reactions varied from 0% to 50.0%. This was significantly higher autoantibody responses to PARP1 and BRCA1/BRCA2 (especially to PARP1 and BRCA1) in ovarian cancer and breast cancer compared to normal control sera (P < 0.001 and P < 0.01). Immunohistochemistry indicated that Pathology Grade at diagnosis to PARP1 expression in breast cancer was different (P < 0.05).

Conclusions

Different cancers have different profiles of autoantibodies. The autoantibodies to proteins involving the synthetic lethal interactions would be novel serological biomarker in some selective cancers.     

Predictive value of BRCA1/2 mRNA expression for response to neoadjuvant chemotherapy in BRCA‐negative breast cancers

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation‐negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real‐time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline‐based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93‐2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane‐based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline‐based treated subgroup (P = .60) or the taxane‐based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation‐negative breast cancer patients who received neoadjuvant anthracycline‐based treatment.     

Improved survival in BRCA2 carriers with ovarian cancer

Objectives The objective of this study was to investigate survival of ovarian cancer patients with BRCA1 and BRCA2 mutations compared to those without mutations in a population-based sample of incident epithelial ovarian cancer cases. Methods Follow-up for vital status was performed on a population-based sample of 232 women with incident epithelial ovarian cancer recruited between December 13, 2000 and September 30, 2003 in the Tampa Bay area. Survival analysis using Cox regression was performed on (1) all 232 cases and (2) the 209 invasive epithelial ovarian cancer cases. Results of the two analyses were similar, thus data involving the 209 invasive epithelial cancer cases are presented, as this was judged to be more clinically relevant. Results In the multivariate analysis, BRCA status and stage were statistically significant, and were adjusted for in the survival analysis model. The Kaplan–Meier method estimated expected survival at 4 years of 83% of BRCA2 carriers compared to 37% of BRCA1 carriers and 12% of non-carriers. There was a statistically significant difference between BRCA2 carriers and non-carriers (p = 0.013). No statistically significant survival differences were seen for BRCA1 carriers when compared with either BRCA2 carriers or non-carriers. Conclusion These data suggest that BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers. The etiology of this possible survival advantage is currently unknown. Larger studies are needed to confirm these results and to clarify their etiology and clinical significance. Article precis Based on a population-based sample of 232 ovarian cancer patients, BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers.