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。     

1例男性乳腺癌患者的临床特征及基因突变分析

目的对1例异时性男性乳腺癌和结肠癌患者及其家系成员进行基因突变分析,以明确病因,便于指导临床风险管理决策。方法采用全外显子测序技术对先证者外周血样本进行基因突变分析,结合表型资料,确定候选基因的可能致病位点。应用Sanger测序技术对先证者及其家系成员候选突变位点进行共分离验证。结果在先证者BRCA2基因第11号外显子中发现c.64026406delTAACT (p.Asn2134fs)杂合突变,该突变在乳腺癌信息中心(BIC)、ClinVar数据库中已有报道,为乳腺癌致病性突变。Sanger测序证实其儿子也为该突变的携带者,而其患结肠癌的母亲未检测到该突变。结论 BRCA2基因c.64026406delTAACT突变是该先证者乳腺癌的致病突变位点,而先证者及其母亲所患结肠癌可能为散发。     

Sonographic features of breast carcinoma presenting as masses in BRCA gene mutation carriers.

OBJECTIVE: The purpose of this study was to review the sonographic features of breast cancer gene BRCA1- and BRCA2-associated breast carcinomas in comparison with "sporadic" breast carcinomas and benign breast masses. METHODS: Sonograms of 233 breast masses, including 33 BRCA-associated malignant masses (BRCA1, 15; BRCA2, 18), 148 sporadic malignant masses, and 52 benign masses, were reviewed by consensus by 2 radiologists according to American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) terminology. RESULTS: Most of the sporadic and BRCA1-and BRCA2-associated cancers displayed an irregular shape (91.2%, 93.3%, and 83.3%, respectively). BRCA1-associated cancers showed microlobulated margins in 53.3% versus 33.8% (sporadic) and 33.3% (BRCA2). A parallel orientation was most frequently encountered in BRCA1-associated lesions (46.7%) versus sporadic (33.8%) and BRCA2 (33.3%), whereas posterior acoustic shadowing was least frequently seen in BRCA1-associated lesions (13.3%) versus BRCA2 (16.7%) and sporadic (31.1%). Most (73.3%) of the BRCA1-associated lesions were classified as BI-RADS category 4, whereas most of the sporadic and BRCA2-associated lesions were classified as BI-RADS category 5 (66.2% and 72.2%). CONCLUSIONS: Sonographic features of BRCA-associated and sporadic breast carcinomas do not differ substantially. BRCA1-associated breast carcinomas trend toward less malignant sonographic characteristics, but strict application of the BI-RADS categorizations demands that they be classified as category 4 or 5.     

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.     

Asymmetric real-time PCR detection of BRCA1 5382insC mutation by melting curve analysis in the LightCycler

BACKGROUND: 5382insC BRCA1 frameshift mutation is a common founder mutation for many populations worldwide and a high-risk allele for the development of hereditary breast and/or ovarian cancer. Our goal was to develop a novel, reliable and rapid method for its detection. METHODS: We developed an asymmetric real-time PCR method with hybridization probes in the LightCycler. Genotyping was performed by melting curve analysis. RESULTS AND CONCLUSIONS: The developed method was in concordance with reference methods when tested in 85 peripheral blood and 107 tumor DNA samples from Greek breast and/or ovarian cancer patients. The described method proved to be simple, cost-effective, easy to perform and rapid enough for routine use as a screening method in high-risk families and especially in the Greek, Slavic and Jewish populations where 5382insC mutation is the most common BRCA1 mutation.     

乳腺癌组织突变型BRCA2的表达及其临床康复意义探讨

目的研究突变型BRCA2在人类乳腺癌组织中的表达及其临床康复意义。方法采用免疫荧光染色技术检测66例手术切除的乳腺癌组织及其癌旁组织中，突变型BRcA2的表达及其与患者临床康复因子间的相关性。结果66例乳腺癌患者的标本中，87．8％（58／66）突变型BRCA2表达上调；12．2％（8／66）肿瘤组织突变型BRCA2表达无显著改变；临床分期越晚与肿瘤分化程度越差者突变型BRCA2的表达指数（LI）值越大；硬癌与浸润癌类型患者突变型BRCA2的LI值较大；有癌转移患者突变型BRCA2的LI值显著高于无转移患者。结论突变型BRCA2的LI与乳腺癌患者的康复因子，如临床分期、肿瘤分化程度、肿瘤病理类型以及有无转移呈显著相关，且突变型BRCA2过表达可能影响乳腺癌患者的康复治疗。     

Receiving inconclusive genetic test results: an interpretive description of the BRCA1/2 experience

We examined the experience of 21 women diagnosed with breast or ovarian cancer who received inconclusive BRCA1/2 genetic test results. Although these women received similar information on the technical meaning of an inconclusive result, their interpretations of personal risk for a probable, inherited cancer mutation differed. Their interpretations ranged from confidence that they probably carried an undetected gene mutation to believing that their cancer had no genetic basis. Women drew from their personal experience with genetic testing and from distinctive perceptions and beliefs in attempting to understand their test results; they variously drew upon such evidence as observations of similarities and differences within familial breast/ovarian cancer patterns to explain their ultimate conclusions as to their own genetic status.     

BRCA1基因与乳腺癌的诊断治疗

乳腺癌易感基因1（BRCA1）是乳腺癌的危险因素之一,是迄今为止发现的与乳腺癌发生相关的最重的抑癌基因。其在遗传性乳腺癌患者中具有高的突变率,已成为国外临床评估女性患乳腺癌风险和指导治疗方案选择的重分子标志物。本文主介绍了BRCA1基因的结构和功能;常用BRCA1基因检测方法,如蛋白质截断测试、单链构象多态性检测、变性高效液相色谱分析技术、多重连接探针扩增技术、高分辨率熔解曲线;BRCA1基因在中国乳腺癌人群中突变情况;BRCA1基因在外科治疗和抗肿瘤药物选择方面中的应用等。     

Performance evaluation of an amplicon-based next-generation sequencing panel for BRCA1 and BRCA2 variant detection

BackgroundAs next‐generation sequencing (NGS) technology matures, various amplicon‐based NGS tests for BRCA1/2 genotyping have been introduced. This study was designed to evaluate an NGS test using a newly released amplicon‐based panel, AmpliSeq for Illumina BRCA Panel (AmpliSeq panel), for detection of clinically significant BRCA variants, and to compare it to another amplicon‐based NGS test confirmed by Sanger sequencing.MethodsWe reviewed BRCA test results done by NGS using the TruSeq Custom Amplicon kit from patients suspected of hereditary breast/ovarian cancer syndrome (HBOC) in 2018. Of those, 96 residual samples with 100 clinically significant variants were included in this study using predefined criteria: 100 variants were distributed throughout the BRCA1 and BRCA2 genes. All target variants were confirmed by Sanger sequencing. Duplicate NGS testing of these samples was performed using the AmpliSeq panel, and the concordance of results from the two amplicon‐based NGS tests was assessed.ResultsNinety‐nine of 100 variants were detected in duplicate BRCA1/2 genotyping using the AmpliSeq panel (sensitivity, 99%; specificity, 100%). In the discordant case, one variant (BRCA1 c.3627dupA) was found only in repeat 1, but not in repeat 2. Automated nomenclature of all variants, except for two indel variants, was in consensus with Human Genome Variation Society nomenclature.ConclusionOur findings confirm that the analytic performance of the AmpliSeq panel is satisfactory, with high sensitivity and specificity.     

BRCA1基因单核苷酸多态性与广东汉族女性散发性乳腺癌易感相关性研究

目的探讨BRCA1基因启动子区rs799906位点和编码区rs799917位点单核苷酸多态性（single nucleotide polymorphism,SNP）与广东汉族女性散发性乳腺癌易感性的关系。方法利用Sequenom Mass Array iPLEX GOLD系统对107例散发性乳腺癌患者及93例健康对照者的BRCA1基因两个SNP位点（rs799906,rs799917）进行检测,并对检测结果进行χ2检验和非条件Logistic回归分析。结果 rs799906位点TT、TC和CC三种基因型在病例组和对照组的分布频率有差异（χ2=8.407,P=0.018）。相对TT基因型而言,TC杂合型能增加乳腺癌发生的危险性（OR=2.566;95%CI：1.101～5.983;P〈0.05）,但等位基因T和C的频率分布无显著差异（χ2=2.169,P=0.141）。rs799917位点CC、CT和TT三种基因型的频率和等位基因C和T的频率在病例组和对照组的分布均无显著性差异（χ2=3.994,P=0.136;χ2=0.903,P=0.342）。结论 BRCA1多态性位点rs799906TC杂合型与散发性乳腺癌发病风险有相关性;而rs799917位点多态性与散发性乳腺癌发病风险无相关性。     

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。     

Successful treatment of refractory lung adenocarcinoma harboring a germline BRCA2 mutation with olaparib: A case report

BACKGROUNDIn recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARYWe describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo).CONCLUSIONThis is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.     

Screening tools for depressed mood after childbirth in UK-based South Asian women: a systematic review

Aim. This paper is a report of a systematic review to answer the question: what is the relevance, acceptability, validity and effectiveness of tools designed to screen for postnatal depressed mood for South Asian women living in the UK? Background. Standard methods to screen women for postnatal depressed mood were developed with Caucasian populations. This study reviews postnatal screening tools adapted or developed for United Kingdom‐based South Asian women. Method. A structured systematic review of English language studies initially was completed between 1980 and May 2003, and later updated to January 2005. The review was based on an a priori search strategy with inclusion and exclusion criteria and analysis included a quality assessment tool. Findings were tabulated against criteria for acceptability and effectiveness of diagnostic tools. Results. Seven papers were included in the review. None addressed all preset quality criteria. Four papers among them reported on translations of two existing tools (Edinburgh Postnatal Depression Scale and General Household Questionnaire). Two new tools were reported between the remaining three papers (Punjabi Postnatal Depression Scale and ‘Doop Chaon’©). Doop Chaon is a visual tool. The other tools used either Bengali or Punjabi, based on written scales. The General Household Questionnaire did not appear to be appropriate for this population. None of the studies were rigorous enough to demonstrate generalizable sensitivity or specificity. Qualitative data indicated that women preferred face‐to‐face interviews to self‐complete questionnaires. Conclusions. None of the tools are currently sufficiently evaluated for clinical practice. Questions are raised specifically about use of language‐based tools to measure postnatal depressed mood in this population and about the extent to which focused interviews could be used as an alternative for specific sub‐sections of population groups.     

The experience of being a psychiatric nurse in South Africa: A qualitative systematic review

Purpose

The purpose of the study was to summarize the experiences of African psychiatric nurses in their workplace by examining the findings of existing qualitative studies.

运动机能贴扎改善乳腺癌术后淋巴水肿疗效的系统评价

目的:系统评价运动机能贴扎(KT)改善乳腺癌术后淋巴水肿的有效性及安全性。方法:计算机检索中国生物医学文献数据库(CBM)、中国期刊全文数据库(CNKI)、维普数据库(VIP)、万方数据资源系统、MEDLINE、EMbase、The Cochrane Library、WHO和PEDro数据库,检索时限均从建库至2016年10月。搜索关于运动机能贴扎改善乳腺癌术后淋巴水肿的随机对照试验。结果:共检索到4篇随机对照试验(Randomized Controlled Trials,RCTs)满足纳入标准,共计162名患者纳入研究。分析结果提示:目前没有足够的证据支持运动机能贴扎能够改善乳腺癌术后患者的淋巴水肿;部分研究结果显示运动机能贴扎可能对淋巴水肿上肢的僵硬感、瘙痒感存在积极作用。结论:运动机能贴扎可能有助于改善淋巴水肿相关症状,但对淋巴水肿程度改善作用尚不明确,期待更多大样本、多中心、高质量的RCTs以验证运动机能贴扎对乳腺癌术后淋巴水肿作用。     

Systemic investigations into the molecular features of bilateral breast cancer for diagnostic purposes

ABSTRACT

Introduction: Many breast cancer (BC) patients develop the disease bilaterally. The emergence of two tumors in the same host is unlikely to be a random co-incidence: bilateral BC (biBC) patients are enriched by women who are susceptible to this disease due to genetic or non-genetic factors.

Areas covered: Data on molecular pathogenesis and translational aspects of biBC research are summarized.

Expert opinion: Studies on concordant and discordant molecular events occurring in paired tumors resemble twin studies, as they help to reveal core components of BC pathogenesis and to analyze interactions between host factors and tumor phenotype. Mutation profiling of biBC pairs suggested that most biBCs are clonally independent malignancies, although some instances of presumably contralateral metastatic spread were shown as well. Many biBCs, especially synchronous ones, demonstrate the similarity of essential tumor characteristics, which can be explained by sharing of genetic background, hormonal milieu, metabolic environment, and external exposures. biBC is strongly associated with BC-predisposing germline mutations; therefore, clinical management of biBC patients must include comprehensive genetic testing. Some contralateral metachronous BCs demonstrate high-level microsatellite instability (MSI-H). MSI-H is sometimes observed in radiation- and chemotherapy-induced tumors; therefore, it is possible that some second BCs are causally related to the therapy applied for the first cancer. MSI-H tumors are responsive to immune checkpoint blockade; hence, MSI-H analysis is advisable for biBC molecular testing. Systematic cataloging of biBC molecular portraits is likely to provide valuable information on fundamental aspects of cancer pathogenesis.     

A novel ATP1A2 mutation in a family with FHM type II

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura with an autosomal dominant pattern of inheritance. Six FHM families underwent extensive clinical and genetic investigation. The authors identified a novel ATP1A2 mutation (E700K) in three patients from one family. In the patients, attacks were triggered by several factors including minor head trauma. In one subject a 3-day coma developed after a cerebral angiography. Overall, the phenotype of the patients closely resembles that of previously reported cases of FHM type II. The E700K variant might be regarded as the cause of the disease in this family, but this was not tested functionally.     

ESR1 mutations: a new biomarker in breast cancer

Introduction: In hormone receptor-positive breast cancer, ESR1 mutations have emerged as a key mechanism of resistance to endocrine therapy.

Areas covered: Here, we review currently available data on ESR1 mutations, regarding their functional impact, prevalence at different stages (and according to the material used: tissue-based analysis vs. liquid biopsy), prognostic impact and predictive value of resistance to aromatase inhibitors. Possible strategies to overcome this resistance by using selective estrogen receptor downregulators (such as fulvestrant) are also discussed.

Expert opinion: ESR1 mutation detection will probably become a prognostic and predictive biomarker in the future, used in clinical practice for hormone-receptor breast cancer, especially in the metastatic setting. In the future, we should expect to assess ESR1 mutations, using liquid biopsy (by digital-PCR or next-generation sequencing), in the same way as other prognostic or predictive biomarkers, such as EGFR mutations in lung cancer, and possibly even have targeted-therapies against these mutations.