伴低级别浆液性癌样成分的混合性子宫内膜样癌:临床病理、免疫表型和基因研究(英)

正作者曾报道2例伴低级别浆液性癌样成分的混合性子宫内膜样癌,它无法被目前基因组分型的4种类型所涵盖。最近,作者又新增1例病例,并对3例进行免疫组化和分子遗传学研究。免疫组化染色项目包括:p53、ER、Ki-67、WT1、MLH1、PMS2、MSH2和MSH6。采用二代测序法检测TP53、KRAS和PIK3CA等基因突变。采用Sanger测序法检测PTEN和POLE等     

高通量测序技术检测乳腺癌患者BRCA1、BRCA2基因的意义

目的采用高通量测序技术检测乳腺癌易感基因(BRCA)1和BRCA2,并探讨BRCA1、BRCA2在家族性乳腺癌筛查中的意义。方法选取7例女性乳腺癌患者及12名健康女性,采用高通量测序技术对BRCA1、BRCA2基因进行测序分析,用Sanger测序法验证检出的位点并对新发BRCA1基因突变位点携带者的家庭成员进行检测。结果 7例乳腺癌患者中,检测出1例致病性突变BRCA2(c.5073dupA),1例可能致病的突变BRCA1(c.3343GT)及1例临床未明意义的突变BRCA2(c.1211AT);12名健康女性中均未检测出BRCA1、BRCA2基因的可疑致病突变位点;携带BRCA1(c.3343GT)突变的家系中有2名乳腺癌患者。结论BRCA1(c.3343GT)是首次发现的遗传性乳腺癌的可能致病性变异位点,其携带者家系中乳腺癌发病率明显升高,建议对其他携带者加强随访,尽早进行手术或药物干预。     

BRCA1与结直肠癌关系的研究进展

乳腺癌易感基因1(breast cancer susceptibility gene 1, BRCA1)是著名的肿瘤易感基因,它编码的蛋白质在正确修复受损DNA中起至关重要的作用。目前国内外关于BRCA1的报道多集中在乳腺癌和卵巢癌的遗传易感性方面,关于BRCA1在结直肠癌（colorectal cancer, CRC）中的效用知之甚少,本文将综述BRCA1基因突变、mRNA及蛋白表达与CRC关系的研究进展及其潜在的治疗作用。     

伴低级别浆液性癌样成分的混合性子宫内膜样癌:临床病理、免疫表型和基因研究

正作者曾报道2例伴低级别浆液性癌样成分的混合性子宫内膜样癌,它无法被目前基因组分型的4种类型所涵盖。最近,作者又新增1例病例,并对3例进行免疫组化和分子遗传学研究。免疫组化染色项目包括:p53、ER、Ki-67、WT1、MLH1、PMS2、MSH2和MSH6。采用二代测序法检测TP53、KRAS和PIK3CA等基因突变,采用Sanger测序法检测PTEN和POLE等基因突变。本组3例患者平均年龄58. 6岁,均未生育且有病态肥胖(体重100～300公斤)。其中1例患者双附件表面出现小转     

预防性切除双附件降低高级别浆液性卵巢癌风险的临床研究

正高级别浆液性卵巢癌是卵巢上皮性恶性肿瘤中最常见的组织学类型,约占70%,大多数患者发现时已是晚期阶段。高达20%的高级别浆液性卵巢癌患者携带基因BRCA1或2的突变,突变患者常常表现为明显的乳腺-卵巢肿瘤家族史[1]。BRCA1或2基因是肿瘤抑制基因,在染色体损伤的修复中     

BRCA1和RAD51在食管鳞癌组织中的表达及临床意义

[目的]探讨乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)和RAD51在食管癌组织中的表达及其意义.[方法]采用SP免疫组织化学法检测120例食管鳞癌和癌旁正常组织及60例上皮内瘤变患者BRCA1和RAD51的表达情况并比较,分析BRCA1和RAD51的阳性表达与临床病理特征间的关系,COX回归分析影响食管鳞癌预后的因素.[结果]BRCA1在食管鳞癌中阳性表达主要定位于细胞质,BRCA1的阳性表达显著高于上皮内瘤变组织和癌旁正常组织(P<0.05).RAD51在食管鳞癌阳性表达定位于细胞核,其阳性表达明显高于上皮瘤变组织和正常食管黏膜组织(P<0.05).相关性分析显示BRCA1与RAD51在食管鳞癌组织中的表达呈正相关(P<0.05).淋巴结转移和RAD51是影响食管鳞癌患者预后的主要因素.[结论]BRCA1和RAD51在食管鳞癌中的阳性表达与患者预后不良有关,有望成为评估食管鳞癌生物学行为新的生物标志物.     

BRCA1和BRCA2基因外显率研究概况

大约5％～10％的乳腺癌与遗传因素有关,在早发性乳腺癌（＜35岁）中,25％ ～ 40％由遗传因素所致,而在这些由遗传因素引起的乳腺癌中,60％ ～ 75％为BRCA1/2胚系突变所致[1-2].全基因组连锁分析和克隆定位已证实,BRCA1和BRCA2是高外显的乳腺癌易感基因.在西方,一般人群到70岁时患乳腺癌的风险约为7％,但若携带BRCAI/2胚系突变基因,携带者到70岁时患乳腺癌的风险显著增高[3].卵巢癌是遗传性乳腺和卵巢癌（hereditary breast and ovarian cancer,HBOC）综合征的突出表型,约48％和27％的遗传性卵巢癌分别由BRCA1和BRCA2突变所致[4].BRCA1/2胚系突变携带者终生患卵巢癌的风险也显著增高[5].此外,BRCA1/2胚系突变与其他一些肿瘤如前列腺癌、胰腺癌等风险增高也有关[5].因而,BRCA1/2基因突变外显率的研究具有重要意义,它可用于评估突变基因携带者患某些肿瘤的风险,从而指导对遗传高危人群的早期诊断和早期预防.通常,外显率指突变携带者到70岁时患某种肿瘤的风险[6].本文将对BRCA1/2突变基因携带者70岁时患乳腺癌、卵巢癌、对侧乳腺癌、男性乳腺癌等肿瘤的风险研究作一综述,为遗传咨询双方提供参考,现综述如下.     

BRCA基因在上皮性卵巢癌中的研究进展

卵巢癌(ovarian carcinoma,OC)是女性患病率和致死率相对较高的肿瘤,其中上皮性卵巢癌(epithelial ovarian cancer,EOC)诊断率明显高于其他类型的OC。EOC的产生与乳腺癌易感基因(breastcancer susceptibility gene,BRCA)有明显的关联性。BRCA基因是一种恶性肿瘤易感基因,可以调整DNA损伤修补,保持细胞生长和细胞凋亡,保持细胞基因遗传稳定性。BRCA基因突变会明显增加患EOC风险,与此同时,BRCA基因影响着EOC的临床诊治、病理和愈后等。具备BRCA基因突变的EOC(BMOC)对铂类DNA损伤剂以及聚腺苷二磷酸核糖聚合酶抑制剂(PARPi)治疗更加敏感。临床上以BRCA基因为主对卵巢癌患者进行多基因检验,可以为卵巢癌的发病机制、风险评价、治疗和愈后提供临床基础。融合最新研究成果,文中就BRCA基因的基本情况以及BRCA基因与上皮性卵巢癌具体关联性作一具体综述。     

深圳地区乳腺癌患者BRCA1基因突变分析

目的研究BRCA1基因在乳腺癌中的突变情况,探讨BRCA1基因突变与乳腺癌的关系。方法应用PCR—SSCP分析和DNA直接测序法,检测57例乳腺癌BRCA1第2,5,11,18,20和21外显子基因突变情况。结果57例中共检测出7例突变,其中4例为11外显子的错义突变（3232A〉G）,3例为20外显子的拼接点突变（IVS20—68insA〉A）。乳腺癌BRCA1的基因突变率为12．2％（7／57）。结论BRCA1基因突变与乳腺癌有密切关系。     

宁夏地区回族女性散发性乳腺癌易感基因BRCA1/BRCA2突变的研究

摘要：目的：研究宁夏地区回族女性散发性乳腺癌中BRCA1/BRCA2基因 (breast cancer susceptibility gene 1/2)的突变位点及携带情况。 方法：收集60例回族居民乳腺癌石蜡包埋组织标本及15例乳腺小叶增生或纤维腺瘤标本。PCR和DNA直接测序法检测BRCA1基因第2、11和20号外显子和BRCA2基因第11号部分外显子突变情况。 结果：60例乳腺癌BRCA1基因有10例突变,突变率为16.7%,突变位点均位于BRCA1基因。15例对照均未检出突变且淋巴结转移与未转移组间BRCA1基因突变率差异（30.8%与5.9%）有统计学意义（P＜0.05）。 结论：BRCA1基因突变可能与宁夏回族女性乳腺癌发生相关。     

Hereditary breast-ovarian cancer: clinical findings and medical management.

Approximately 5% to 10% of breast and ovarian cancers are related to an inherited gene mutation. Of these cases, 84% of hereditary breast cancer and more than 90% of hereditary ovarian cancer are caused by mutations in the BRCA1 or BRCA2 genes. Family histories of cancer are an essential tool in identifying features of and individuals at risk for hereditary breast-ovarian cancer syndrome. The risk to carry an identifiable BRCA gene mutation can be assessed by trained healthcare providers using various pre-test risk models. Individuals who carry a BRCA gene mutation have increased lifetime risks of developing hereditary breast and ovarian cancer syndrome-related cancers. Genetic testing for the BRCA gene mutations is offered in accordance with American Society of Clinical Oncology guidelines. In accordance with guidelines, patients are informed of the risks, benefits, and limitations of testing prior to electing to undergo the testing process. Upon receipt of results, healthcare providers offer the patient with appropriate medical management recommendations.     

BRCA1 gene mutations in sporadic ovarian carcinomas: detection by PCR and reverse allele-specific oligonucleotide hybridization.

BACKGROUND: Although germline mutations in BRCA1 play a central role in familial breast and ovarian cancers, to date, no somatic mutations in BRCA1 have been reported in sporadic breast cancer, and only five somatic mutations have been identified in the sporadic ovarian carcinomas. Because loss of heterozygosity appears frequently at the BRCA1 locus in nonfamilial breast and ovarian carcinomas, we searched for mutations in the BRCA1 gene in sporadic ovarian tumors. METHODS: We developed a detection system based on PCR and reverse allele-specific oligonucleotide hybridization on membrane strips for the simultaneous detection of 17 frequently occurring mutations in the BRCA1 gene. RESULTS: As little as 2% mutant DNA in a sample could be detected. Two of 122 DNA samples isolated from sporadic ovarian tumor biopsies contained the Cys61Gly mutation. Both mutations were germline mutations. One of these was an ovarian metastasis of a primary fallopian tube carcinoma. The tubal carcinoma was also confirmed to contain the Cys61Gly mutation. CONCLUSIONS: This is the first report that a germline BRCA1 mutation is associated with primary tubal carcinoma. The 17 specific mutations in the BRCA1 gene do not play a major role in the tumorigenesis and progression of sporadic ovarian cancer.     

Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases

Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ～80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3' EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation.     

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.     

Long-Range PCR and Next-Generation Sequencing of BRCA1 and BRCA2 in Breast Cancer

Individuals and families carrying mutations in BRCA1 and BRCA2 (BRCA1/2) have a markedly elevated risk of developing breast and ovarian cancers. The first-generation of BRCA1/2 mutation analysis targeted only the coding exons and has implicated protein-truncating mutations (indel, nonsense) in BRCA1/2 inactivation. Recently, heritable breast cancers have also been attributed to other exonic mutations (missense, silent) and mutations in introns and untranslated regions. However, analysis of these alterations has been prohibitively laborious and cost intensive, and the proportion of cases carrying mutations in unscreened regions of BRCA1/2 and other predisposition genes is unknown. We have developed and validated a next-generation sequencing (NGS) approach for BRCA1/2 mutation analysis by applying long-range PCR and deep sequencing. Genomic DNA from familial breast cancer patients (N = 12) were screened and NGS successfully identified all 19 distinct (51 total) BRCA1 and 35 distinct (63 total) BRCA2 sequence alterations detectable by the Sanger sequencing, with no false-negative or positive results. In addition, we report the robust detection of variants from introns and untranslated regions. These results illustrate that NGS can provide comprehensive genetic information more quickly, accurately, and at a lower cost than conventional approaches, and we propose NGS to be a more effective method for BRCA1/2 mutational analysis. Advances in NGS will play an important role in enabling molecular diagnostics and personalized treatment of breast and ovarian cancers.     

BRCA1 at the crossroad of multiple cellular pathways: approaches for therapeutic interventions

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 genes. Low expression of these genes in sporadic tumors extends their significance to sporadic breast and ovarian cancers as well. For over a decade since its identification, extensive research has been directed toward understanding the function of the breast and ovarian tumor suppressor gene BRCA1. The long-term goal has been to identify the biochemical pathways reliant on BRCA1 that can be exploited for developing targeted therapies and benefit mutation carriers. To date, no one specific role has been identified, but rather it is clear that BRCA1 has significant roles in multiple fundamental cellular processes, including control of gene expression, chromatin remodeling, DNA repair, cell cycle checkpoint control, and ubiquitination, and overall is important for maintenance of genomic stability. Major findings and potential BRCA1-dependent therapies will be discussed.     

Hereditary breast cancer: high risk genes, genetic testing and clinical implications

About one in eight to ten women living in Western countries will develop breast cancer during her lifetime and between 5-10% of these cases result from an inherited susceptibility to the disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, TP53, PTEN, MLH1, MSH2, and STK11. The identification of these genes, together with the rapid advances in molecular genetic analyses, should improve the diagnosis and therapy of breast cancer. This article reviews the genetic basis of hereditary breast cancer, in particular the contribution of BRCA1 and BRCA2 and discusses the clinical application of this new molecular knowledge with regard to molecular testing, surveillance and prevention in women with a hereditary predisposition to breast cancer.     

BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses

PURPOSE: The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. DATA SOURCES: Data sources include reviews and original research from scholarly journals and Internet sites. CONCLUSIONS: Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. IMPLICATIONS FOR PRACTICE: NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.