BRCA1在乳腺癌和癌前病变中的表达和意义

目的 检测乳腺癌易感基因１（ＢＲＣＡ１）在乳腺癌发生,发展中的变化状况、分析该基因与ｐ５３基因、ＥＲ、ＰＲ表达的关系,进一步探讨其在乳腺癌发生发展中的作用。方法 应用乳腺常规切片技术,结合免疫组织化学法（ＩＨＣ）检测乳腺癌和癌前病变（１００例,共２３２个病灶）中ＢＲＣＡ１表达状况,同时对６３例乳腺癌中ＢＲＣＡ１与ｐ５３基因、雌激素受体（ＥＲ）、孕激素受体（ＰＲ）表达的关系进行研究。结果 （１）乳腺     

38例散发乳腺癌患者BRCA1基因突变检测

目的：分析３８例散发乳腺癌患者ＢＲＣＡ１基因突变情况及突变位置。方法：应用ＰＣＲ－ＳＳＣＰ（Ｓｉｎｇｌｅ－ｓｔｒａｎｄｅｄ ｃｏｎｆｏｒｍａｔｉｏｎａｌ ｐｏｌｙｍｏｒｐｈｉｓｍ,ＳＳＣＰ）和直接测序方法。结果：４／３８例患者ＢＲＣＡ１基因有突变,突变例数占总例和的１０．５％,其中３例突变位置在内含子的拼接区,一例突变位置在１１号外显子上。结论：筛查ＢＲＣＡ１基因突变对于乳腺癌患病风险评估,发病检     

新鲜乳腺疾病组织CerbB—2基因蛋白表达,癌胚抗原,性激素受体的研究

应用ＡＢＣ法对４２例乳腺癌，４０例乳腺良性新鲜冰冻组织进行了ＣｅｒｂＢ－２基因蛋白表达的研究，比较了Ｃ－ｅｒｂＢ－２，雌激素受体（ＥＲ），孕激素受体（ＰｇＲ），癌胚抗原（ＣＥＡ）在乳腺癌组织中的表达。结果：乳腺癌中２６例（６１．９％）有ＣｅｒｂＢ－２基因表达，强阳性表达８例（１９．０％），良性乳腺病变也有表达；淋巴结转移多见于ＣｅｒｂＢ－２阳性，ＥＲ阳性，ＣＥＡ阴性病例；随着Ｃ－ｅｒｂＢ－２表达程     

新鲜乳腺疾病组织C－erbB－2基因蛋白表达、癌胚抗原、性激素受体的研究

应用ＡＢＣ法对４２例乳腺癌、４０例乳腺良性病变新鲜冰冻组织进行了Ｃ－ｅｒｂＢ－２基因蛋白表达的研究，比较了Ｃ－ｅｒｂＢ－２、雌激素受体（ＥＲ）、孕激素受体（ＰｇＲ）、癌胚抗原（ＣＥＡ）在乳腺癌组织中的表达。结果：乳腺癌中２６例（６１．９％）有Ｃ－ｅｒｂＢ－２基因表达，强阳性表达８例（１９．０％），良性乳腺病变也有表达；淋巴结转移多见于Ｃ－ｅｒｂＢ－２阳性、ＥＲ阴性，ＣＥＡ阴性病例；随着Ｃ－ｅｒｂＢ－２表达程度增加（－→＋→＋＋），淋巴结转移阳性率增加，临床分期为Ｉ期的患者数减少，ＩＩ、ＩＩＩ期增多，ＥＲ、ＰｇＲ受体水平下降。提示，Ｃ－ｅｒｂＢ－２基因蛋白表达与预后有关，表达强度越高，预后越差。     

乳腺癌易感癌基因BRCA1与p53的免疫组化研究

目的：探讨ＢＲＣＡ１在家族性乳腺癌中的作用及其与ｐ５３的相关性。方法：对家族性乳腺癌手术标本及非家族性乳腺癌手术标本共８４例ＢＲＣＡ１及ｐ５３蛋折免疫组化（Ｓ－Ｐ法）检测。结果：ＢＲＣＡ１在家族乳腺癌中及非家族性乳腺中的阳性率分别为６１．９％和１１．９％,ｐ５３在家族性乳腺癌及非家族乳腺癌中的阳性率分别为４０．５％和２６．２％,而在家族性乳腺癌ＢＲＣＡ１阳性病例中有５７．７％的病例ｐ５３阳性,在非     

c—erbB—2、nm23及PCNA蛋白在乳腺肿瘤中的表达及意义

目的：探讨ｃ－ｅｒｂＢ－２、ｎｍ２３及ＰＣＮＡ蛋白在乳腺有关肿瘤中的表达情况及意义。方法：应用免疫组化Ｓ－Ｐ法，对１３１例乳腺良恶性肿瘤进行ｃ－ｅｒｂＢ－２、ｎｍ２３和ＰＣＮＡ蛋白检测，对其中１０２例乳腺癌进行雌激素受体（ＥＲ）和孕激素受体（ＰＲ）检测。结果：ｃ－ｅｒｂＢ－２蛋白在导管内癌、Ｐａｇｅｔ病及浸润性导管癌中呈高表达；ｎｍ２３蛋白在浸润性小叶癌中呈高表达；ＰＣＮＡ在导管内癌、髓样癌及粘液腺癌中呈高表达。ｃ－ｅｒｂＢ－２与淋巴结转移及ＰＲ呈正相关；ｎｍ２３与乳腺癌患者的年龄、组织学分级、淋巴结转移及ＥＲ和ＰＲ密切相关。ＰＣＮＡ与肿瘤组织的坏死明显相关。结论：不同组织学类型乳腺肿瘤可能由不同的癌基因以不同的组合方式发生突变所致。ｃ－ｅｒｂＢ－２呈阴性表达而ｎｍ２３呈阳性表达时，乳腺癌患者的预后最好。     

乳腺肿瘤中C—erbB—2癌基因蛋白的表达及意义

目的：探讨Ｃ－ｅｒｂＢ－２癌基因蛋白在乳腺中肿瘤中的表达情况及临床意义。方法：应用免疫组化ＳＰ法,对１２６例乳腺良恶性肿瘤进行Ｃ－ｅｒｂＢ－２癌基因蛋白检测,其中９７例乳腺癌进行激素受体（ＥＲ）和孕激素受体（ＰＲ）检测。结果：Ｃ－ｅｒｂＢ－２蛋白阳性表达的细胞主要为癌细胞。Ｃ－ｅｒｂＢ－２蛋白在导管内癌、Ｐａｇｅｔ‘ｓ蛋白在导管内癌Ｐａｇｅｔ’ｓ病是浸润性导管癌中呈高表达,在浸润的小叶癌中均呈阴性     

青年乳腺癌易感基因突变与淋巴结转移相关性研究

目的：了解青年乳腺癌ＢＲＣＡ１基因突变情况,探讨ＢＲＣＡ１基因突变与腋窝淋巴结转移等临床病理参数的关系。方法：应用聚合酶链式反应（ＰＣＲ）－变性聚丙烯酰胺凝胶电泳（ＰＡＵＧＥ）－ＤＮＡ银染方法,研究３０例〈３５岁乳腺癌患者的ＢＲＣＡ１基因外显子２、２０的突变情况。结果：检出８全 变,突变率为２６．７％,５例在外显子２,３例在外显子２０。腋窝淋巴结转移的乳腺癌ＢＲＣＡ１突变率为３８．９％,而无转移者     

Analysis of the mutations of BRCA1 gene in 38 breast cancer patients

目的： 分析３８ 例散发乳腺癌患者 Ｂ Ｒ Ｃ Ａ１ 基因突变情况及突变位置。方法： 应用 Ｐ Ｃ Ｒ Ｓ Ｓ Ｃ Ｐ（ Ｓｉｎｇｌｅｓｔｒａｎｄｅｄ ｃｏｎｆｏｒｍａｔｉｏｎａｌ ｐｏｌｙｍｏｒｐｈｉｓｍ , Ｓ Ｓ Ｃ Ｐ） 和直接测序方法。结果：４／３８ 例患者 Ｂ Ｒ Ｃ Ａ１ 基因有突变,突变例数占总例数的１０ ．５ ％ ,其中３ 例突变位置在内含子的拼接区,一例突变位置在１１ 号外显子上。结论：筛查 Ｂ Ｒ Ｃ Ａ１ 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。     

应用MEIA技术检测乳腺癌患者血清CA15-3水平

应用ＭＥＩＡ技术检测乳腺癌患者血清ＣＡ１５－３水平何丽容冯海林黄育昌关键词乳腺肿瘤ＣＡ１５－３酶免疫微粒子技术中图号Ｒ７３０．４３ＣＡ１５－３是一种乳腺癌相关抗原，近年来国外已有放免方法测定ＣＡ１５－３的报道〔１～３〕。我们应用酶免疫微粒子分析技术（...     

Breast tumor immunophenotype of BRCA1-mutation carriers is influenced by age at diagnosis.

PURPOSE: Breast tumors of BRCA1 mutation carriers and those of early onset breast cancer cases share similar histological features, being generally high-grade, highly proliferative, aneuploid tumors that are predominantly estrogen- and progesterone-receptor negative. Because histological features of tumors of premenopausal women differ from those of tumors of older women, we sought to determine whether the immunophenotype of breast tumors of BRCA1 mutation carriers was influenced by age at diagnosis. EXPERIMENTAL DESIGN: We examined 31 breast tumors from BRCA1 mutation carriers and compared them with 81 tumors of age-matched (plus or minus 5 years) breast cancer patients unselected for family history. Tumors were further matched for histology, grade, and size. Paraffin-embedded tumor tissues were examined for protein expression of estrogen receptor (ER), PR, Ki-67, cyclin D1, TP53, HER2, beta-catenin, and cyclin E using immunohistochemical approaches. RESULTS: ER (P = 0.01), PR (P = 0.06), and cyclin D1 (P = 0.002) were less frequently expressed and Ki-67 (P = 0.01) and beta-catenin (P = 0.04) were more frequently expressed in tumors of BRCA1 mutation carriers than controls. After age stratification, we found a significant difference in the frequency of tumors of BRCA1 mutation carriers diagnosed before 50 years of age compared with age-matched controls that stained positive for ER (P = 0.01), PR (P = 0.03), Ki-67 (P = 0.008), cyclin D1 (P < 0.001), HER2 (P = 0.04), and beta-catenin (P = 0.05). However, no significant differences were observed in tumors of BRCA1 mutation carriers diagnosed at age 50 or older compared with age-matched controls. CONCLUSIONS: These data suggest that age at diagnosis, possibly related to menopausal status, may be an important factor in the expression of specific proteins in breast tumors of BRCA1 mutation carriers.     

基于基因瘢痕评分(GSS)探索乳腺癌中的同源重组修复缺陷(HRD)

目的:使用基因瘢痕评分(GSS)描述中国乳腺癌人群的HRD状态,并对乳腺癌的HRD状态和临床特征进行统计学分析。方法:使用AmoyDx HRD Panel检测我院诊断的79例乳腺癌患者。根据拷贝数长度(LCN)、拷贝数部位(SCN)和拷贝数类型(TCN)确定基因组疤痕得分(GSS)。HRD阳性是指BRCA突变阳性和/或GSS得分≥50。HRD得分与临床特征之间的关系通过卡方检验和Fisher's精确检验及Wilcoxon秩和检验进行统计分析。结果:在79例患者中,BRCA突变阳性率10.1%,HRD阳性率35.4%。在TNBC患者中,HRD阳性率为80%,BRCA突变阳性率26.7%。53.4%的TNBC患者BRCA突变阴性但HRD阳性。与HRD阴性的乳腺癌相比,HRD阳性乳腺癌明显更可能是Ki-67高(P<0.05)、ER阴性(P<0.05)和PR阴性(P<0.05)的肿瘤。HRD阳性率在TNBC(80%)中也明显高于Luminal A(7.7%,P<0.001)和Luminal B(27.7%,P<0.05)。结论:GSS是乳腺癌同源重组缺陷的重要检测工具,能帮助挖掘BRCA突变阴性但HRD阳性的乳腺癌人群。HRD状态与乳腺癌的ER、PR和Ki-67状态相关。     

河北省家族性和散发性乳腺癌易感基因1/2突变的研究

目的探讨河北省家族性和散发性乳腺癌患者乳腺癌易感基因(BRCA)1/2的突变位点及携带情况。方法采用聚合酶链反应-单链构象多态性分析和基因测序技术对18例家族性乳腺癌患者、50例散发性乳腺癌患者、23例乳腺良性疾病患者及20例健康对照组血样标本的基因组DNA进行BRCA1/2基因突变的检测。定性资料采用χ2检验和Fisher's确切概率法进行分析,定量资料采用t检验进行分析。结果 68例乳腺癌患者基因突变率为7.35%(5/68),均发生在BRCA1基因(162ATTTTT;4142GTTGTG;4196CAACAT;4196delA,4142GTTGTG;5379GAAAAA),无BRCA2基因突变,BRCA1基因的突变率高于BRCA2基因(χ2=4.829,P=0.028);其中,18例家族性乳腺癌基因突变3例,50例散发性乳腺癌突变2例,二者间差异无统计学意义(χ2=3.117,P=0.111)。乳腺良性疾病患者未见BRCA1/2基因突变。健康对照组未见BRCA1基因突变,但有1例BRCA2基因突变[TTTCAGA-TGTCAA(6291insG,6294delG)]。家族性乳腺癌患者、散发性乳腺癌患者、乳腺良性疾病患者和健康对照组的BRCA1基因突变率差异有统计学意义(χ2=8.248,P=0.041)。在1例家族性乳腺癌标本中发现1个核苷酸多态性位点,位于BRCA1第20外显子下游第35个碱基处GA(IVS20+35GA)。结论本研究丰富了中国人群BRCA1/2基因的突变谱,并为将来乳腺癌的普查和临床基因检测提供了筛查模式。     

BRCA1 germline mutation in a woman with metaplastic squamous cell breast cancer

BACKGROUND: Breast cancers arising in women with germline BRCA1 mutations are most likely to be estrogen receptor (ER), progesterone receptor (PR), and HER2/neu negative (so-called triple negative or basal-like breast cancers). Metaplastic carcinoma with pure squamous differentiation is a very rare histological subtype (0.1% of all breast cancers) and is usually ER, PR, and HER2/neu negative by immunohistochemistry. A BRCA1 germline mutation in squamous cell breast cancer has never been reported. CASE REPORT: A 25-year-old woman was diagnosed with squamous cell cancer of the breast. Three years later, she developed contralateral breast cancer, also of the squamous cell subtype. Both tumors were triple negative. Because of the patient's history and her strong family history, genetic testing was recommended. The patient was found to be carrier of a BRCA1 germline mutation. CONCLUSION: We report, to our knowledge, the first case of a BRCA1 mutation in a woman with metaplastic squamous cell breast cancer.     

BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer

The data related to BRCA1 germline mutation in Chinese women with familial breast cancer is increasing. However, little is known the frequency of BRCA1 mutations in Chinese women with familial or early-onset breast cancer from Northern China, and few studies are available to investigate the clinicopathological characteristics of BRCA1 tumors in Chinese women. In this study, we detected germline mutations in BRCA1 in a cohort of 139 breast cancer patients who either have a family history of breast cancer (n = 68) or whose tumors are diagnosed at or before the age of 35 (n = 71) from Northern China. A total of 6 deleterious BRCA1 mutations were identified in this cohort, 4 of which (5587-1 del8, 3887 del AG, IVS21 + 1delG, and 2129 ins TG) are novel and one mutation (3478del5) detected in this study was only reported in Chinese population. The frequency of BRCA1 mutations in women with familial or early-onset breast cancer was 5.9% (4/68) or 2.8% (2/71) in this cohort, respectively; but the mutations were detected in 4 of 16(25.0%) familial breast cancer patients whose tumors were diagnosed before the age of 40. Moreover, BRCA1 mutation tumors tended to be high histological grade, and to be negative for ER, PgR, and Her-2 compared with tumors without BRCA1 mutations. Our study suggests that Chinese women with a family history of breast cancer whose tumors are diagnosed before age of 40 would be a suitable candidate for BRCA1 testing; and BRCA1 tumors in Chinese women exhibit an aggressive phenotype. W. Chen and K. Pan contributed equally to this study.     

家族性和早发性乳腺癌BRCA1基因突变分析

目的 分析中国黑龙江省家族性和早发性乳腺癌中BRCA1基因的突变情况。方法 以黑龙江地区的92例家族性和早发性乳腺癌(发病年龄≤35岁)为研究对象。由静脉血提取基因组DNA,对BRCA1基因的全部编码序列(除外1,4号外显子)进行扩增。由聚丙烯酰胺凝胶电泳分析(SSCP)进行突变的初筛,之后进行DNA直接测序证实。结果 在92例乳腺癌患者中发现有5种致病性突变,其中3种为新发现的突变,发现的已报道的2种突变均为无义突变。结论 在中国黑龙江人群中,BRCA1基因的突变对于遗传性乳腺癌的发生可能具有较重要意义;新发现的3个突变位点可能是中国人群中的特有突变;黑龙江地区BRCA1在家族性乳腺癌中突变率明显低于国内外报道,但其中的移码突变3712insG分别在3个患者中检出,提示有可能成为该地区的基础突变。     

Relative contributions of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations to “triple-negative” breast cancer in Ashkenazi Women

Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry a founder mutation in BRCA1 or BRCA2. There is an association between BRCA1 mutations and “triple-negative” breast cancer (TNBC) [estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative]. We sought to determine the predictive value of the TNBC phenotype for the presence of a BRCA mutation in AJ women ascertained without respect to family history. DNA samples were collected between 8/2000 and 6/2004 from a prevalent cohort of unselected AJ women with breast cancer (median age at diagnosis 56 years). Samples (n = 451) were genotyped for AJ founder mutations. 352 (78.0%) cancers were ER positive, 254 (56.3%) PR positive, and 91 (20.2%) ER negative/PR negative. 63 (14.0%) cancers were HER2 positive (immunohistochemistry 3+ or FISH >2.2). TNBC was observed in 64 patients (14.2%). Founder mutations were detected in 48 samples (10.6%) including 25/64 TNBC (39.1%; 19 BRCA1, 6 BRCA2). Among TNBC patients with family history (FH) information, 6/15 (40%) mutations were found in women without breast or ovarian cancer in a close relative. The positive predictive value of TNBC for a BRCA1 mutation was 30% overall, 50% in women diagnosed<50 years, and 14% in women diagnosed ≥50. TNBC was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TNBC. The prevalence of BRCA founder mutations exceeds 50% in subsets of AJ women with TNBC. FH is an imperfect predictor of mutation status in this group. A significant number of mutation-associated TNBC are due to BRCA2.     

中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究

背景与目的：BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法：回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果：BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论：中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。     

Basal cytokeratins in breast tumours among BRCA1, BRCA2 and mutation-negative breast cancer families

Introduction

Finding new immunohistochemical markers that are specific to hereditary breast cancer could help us to select candidates for BRCA1/BRCA2 mutation testing and to understand the biological pathways of tumour development.

Methods

Using breast cancer tumour microarrays, immunohistochemical expression of cytokeratin (CK)-5/6, CK-14 and CK-17 was evaluated in breast tumours from BRCA1 families (n = 46), BRCA2 families (n = 40), non-BRCA1/BRCA2 families (n = 358) and familial breast cancer patients with one first-degree relative affected by breast or ovarian cancer (n = 270), as well as from patients with sporadic breast cancer (n = 364). Staining for CK-5/6, CK-14 and CK-17 was compared between these groups and correlated with other clinical and histological factors.

Results

CK-5/6, CK-14 and CK-17 were detected mostly among oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and high-grade tumours. We found the highest percentages of samples positive for these CKs among ER-negative/HER2-negative tumours. In univariate analysis, CK-14 was significantly associated with tumours from BRCA1 (39%; P < 0.0005), BRCA2 (27%; P = 0.011), and non-BRCA1/BRCA2 (21%; P < 0.005) families, as compared with sporadic tumours (10%). However, in multivariate analysis, CKs were not found to be independently associated with BRCA1 or BRCA2 mutation status, and the most effective predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status.

Conclusion

Although our study confirms that basal CKs can help to identify BRCA1 mutation carriers, this effect was weaker than previously suggested and CKs did not independently predict BRCA1 mutation either from sporadic or familial breast cancer cases. The most effective, independent predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status, as compared with sporadic or non-BRCA1/BRCA2 cancers.