BRCA1和BRCA2在胶东半岛地区女性散发性乳腺癌中的表达研究

Objective To study the expression and clinical significance of BRCA1 and BRCA2 in sporadic breast cancer in women of Jiaodong peninsula. Methods Immunohistochemistry and tissue array were used to detect the expression of BRCA1 and BRCA2 in 100 cases of sporadic breast cancer and 30 cases of benign breast tumor in women of Jiaodong peninsula. Results ① The expression rate of BRCA1 and BRCA2 was 49% (49/100) and 50% (50/100) in breast cancer, 80% (24/30) and 83.33% (25/30) in benign breast lesions respectively. The expression rate of BRCA1 and BRCA2 in breast cancer was lower than that in benign breast lesions (P<0.05). ② The expression of BRCA1 and BRCA2 was uncorrelated with factors such as tumor size, lymphatic metastases, age and menopause or not(P>0.05). ③ There was no dependency between the expression of BRCA1 and BRCA2 (P> 0. 05). Conclusions The expression rate of BRCA1 and BRCA2 in breast carcinoma in women of Jiaodong peninsula was lower than that in benign breast lesions, suggesting that the expression of BRCA1 and BRCA2 was related to the occurrence of sporadic breast carcinoma in women of Jiaodong peninsula. However, the role of BRCA1 and BRCA2 in the genesis and development of the breast carcinoma is independent.     

Functional Domains of the BRCA1 and BRCA2 Proteins

The BRCA1 and BRCA2 genes encode large unrelatedproteins that presumably function as tumor suppressorsin normal epithelial cells of the breast. However, theprimary amino acid sequences of these proteins provide few insights into the mechanisms bywhich BRCA1 and BRCA2 inhibit tumor development.Nevertheless, recent studies have uncovered manysimilarities in the biological properties of BRCA1 andBRCA2, raising the prospect that these proteins mayfunction in a common pathway of tumor suppression andthat inactivation of either gene may represent anequivalent step in the development of breast cancer. Several lines of evidence now suggest a rolefor BRCA1 and BRCA2 in the cellular response to DNAdamage, possibly by virtue of their relationship withproteins required for the recombinational repair of double-strand DNA breaks. Accordingly, the lossof BRCA1 or BRCA2 function might accelerate tumordevelopment by allowing cells to accumulate DNA lesionsthat are potentially oncogenic.     

The role of BRCA1 and BRCA2 in prostate cancer

One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men ≤65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.     

Screening and Clinical Implications for BRCA1 and BRCA2 Mutation Carriers

In this article, we review the history oftesting for mutations in breast cancer susceptibilitygenes and discuss the current state of testing formutations in BRCA1 and BRCA2 in different clinicalsettings including at-risk individuals and cancerpatients. The risk of breast cancer, other associatedmalignancies and prognosis in carriers of thesemutations are reviewed. A final section includesdiscussion of current recommendations for surveillance andthe need for further research to identify environmentaland genetic factors which modify the risk of developingcancer in mutation carriers.     

The prevalence of germline BRCA1 and BRCA2 mutations in young women with breast cancer undergoing breast-conservation therapy

BACKGROUND: Germline mutations of BRCA1 and BRCA2 increase the risk for breast cancer. Mutation carriers selecting breast-conservation therapy (BCT) for treatment of operable breast cancer experience a higher rate of new primary breast cancers. We sought to determine the frequency of BRCA1/BRCA2 mutations in women who underwent BCT. Genetic testing results were compared with the prior probability of mutations in either gene. METHODS: Eighty-nine patients age 39 or younger entered the study. Genetic testing was performed for BRCA1 and BRCA2 and the BRCAPRO model determined the probability of carrying a mutation. RESULTS: Eight mutations were discovered (prevalence, 9.0%). Twenty (22%) uncharacterized sequence variants were found. The prior probability of carrying a mutation was 14%. Mutation carriers had a higher prior probability (.49) compared with women with uncharacterized variants (.09) or with normal genes (.11). CONCLUSIONS: BRCA1 and BRCA2 mutations are common (9%) among unselected young breast cancer patients undergoing BCT.     

散发性乳腺癌中BRCA1和BRCA2基因突变的研究

目的检测BRCA1和BRCA2基因在散发性乳腺癌中的突变情况,探讨BRCA1和BRCA2基因突变与乳腺癌的关系。方法选取2000年12月至2005年9月收治的144例乳腺癌患者标本作实验组,另取非癌乳腺组织标本30例作对照组。用酚-氯仿抽提法提取DNA。针对各个外显子的碱基序列特征,设计有助于筛查基因碱基突变的聚合酶链反应（PCR）引物。每例DNA标本均用PCR扩增BRCA1基因的全部22个外显子和BRCA2基因的exon10和exon14两个外显子。分别将每例外显子的PCR扩增产物进行单链构象多态性分析,对泳动变位或出现异常区带的PCR扩增产物进行DNA测序。结果对照组未检测出BRCA1和BRCA2基因突变,实验组中检测出20例BRCA1基因碱基改变,总突变率为13．9％,其中错义突变率为11．1％。BRCA2基因exon10和exon14未检测出突变。结论BBCA1突变与乳腺癌密切相关,筛查BRCA1基因突变对于中国人群乳腺癌患病风险评估、早期诊断及基因治疗具有重要意义。     

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers.Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression.ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively).ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.     

Nonsurgical Prevention Strategies in BRCA1 and BRCA2 Mutation Carriers

BackgroundFemale carriers of a BRCA1 or 2 germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.SummaryWhile endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, BRCA1-deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in BRCA1-deficient mouse models.Key MessageThe prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers.     

BRCA1 und BRCA2: Mutationen und andere genetische Veränderungen – praktische Relevanz

Zusammenfassung. Bei 5–10 % aller an Mammacarcinom erkrankten Frauen ist die Erkrankung auf eine genetische Disposition zurückzuführen. Innerhalb der letzten 10 Jahre sind die wichtigsten disponierenden Gene für Mammacarcinom, BRCA1 und BRCA2, identifiziert worden. Beide Gene sind Tumorsuppressorgene, deren Funktion bislang noch nicht vollst?ndig aufgekl?rt ist. Die Gendiagnostik von BRCA1 und BRCA2 bildet die Grundlage, das Erkrankungsrisiko für Frauen aus Risikofamilien mit Mammacarcinom zu bestimmen und wird wichtige Informationen zur Pr?vention und Behandlung von erblichem Mammacarcinom geben.      

Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic

BACKGROUND: Male BRCA1 and BRCA2 mutation carriers are at an increased risk to develop prostate cancer and are subject to screening protocols for high-risk men. The utility of targeted screening, and the clinical and pathological features associated with prostate cancer, have received little attention in this population. METHODS: We report on the clinical screening and pathological characteristics of a group of 19 men with BRCA1 or BRCA2 mutation, as compared to an age-matched group of men with a family history of prostate cancer. RESULTS: Mutation carriers were significantly more likely to have an elevated PSA at first visit (P = 0.03). Prostate cancer was twice as likely to be diagnosed in mutation carriers although this difference was not statistically significant (P = 0.55). CONCLUSIONS: Prostate cancer surveillance of BRCA1 and BRCA2 mutation carriers is warranted. Further research on larger cohorts is needed to evaluate whether unique pathological prostate cancer characteristics exist in these men.     

Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer

Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes. It is an autosomal dominantly inherited disorder with variable expression that is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2 or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen syndrome have an increased risk of developing breast cancer. Here we have analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to study whether a proportion of these families might have mutations in Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no pathogenic mutations in the coding sequence in any of the 26 patients. MLPA (multiplex ligation-dependent probe amplification)-analysis also showed no alterations in copy numbers in any of the craniofacial disorder genes MSX2, ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our findings indicate that mutations in Saethre-Chotzen-associated genes are uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer.     

DNA损伤对前列腺癌细胞株BRCA1蛋白表达的影响

目的:探讨肿瘤抑制基因BRCA1对DNA损伤的反应中的重要作用。明确BRCA1蛋白除了受转录控制、磷酸化和蛋白相互间作用等机制调节外,其功能也受BRCA1的亚细胞分布的功能调节。方法:以乳腺癌细胞株作为阳性对照组,对前列腺癌细胞株LNCaP,DU145和PC-3的BRCA1亚细胞分布免疫荧光染色,并对BRCA1的表达量进行Western印迹检测。结果:BRCA1蛋白存在于LNCaP,DU145和PC-3的前列腺癌细胞株中,而且DNA损伤后能够引起其出核现象,即BRCA1蛋白在细胞质的细胞分布比例由14%增加到40%(P<0.01),相反在细胞核其分布比例由46%减少到21%(P<0.01)。BRCA1这种DNA损伤后的胞质亚细胞分布比例增高仅在p53野生型前列腺癌细胞株出现,在p53突变型前列腺癌细胞株没有此现象。形态学和Western印迹法证实,LNCaP细胞DNA损伤后BRCA1蛋白在胞质、胞核间互动后其凋亡比例高达40%,细胞凋亡的标记蛋白(裂解后caspase-3活性片段)也明显增高。结论:BRCA1的胞质胞核重新分布可能是DNA损伤后的蛋白功能调节机制之一;BRCA1这种亚细胞分布改变需要p53的功能调节,与p53的状态及其功能相关,同时也引起细胞凋亡比例的提高。在前列腺癌细胞株BRCA1引起更高比例的细胞凋亡现象预示,BRCA1可能成为前列腺癌临床治疗的生物靶点。     

Awareness and attitudes concerning BRCA gene testing

Background: The availability of a commercial test for the breast cancer susceptibility genes, BRCA1 and BRCA2, has generated interest in both the medical community and the general public. Methods: Patients and family members were approached in the waiting room and asked to fill out an anonymous questionnaire about their awareness of breast cancer genes and breast cancer gene testing, and their desire to be tested. ² analysis was used to analyze frequencies between groups. Results: A total of 354 women completed a questionnaire concerning the breast cancer genes BRCA1 and BRCA2. The very young, the very old, and African-Americans were the least informed in terms of awareness of the genes and the availability of testing for the breast cancer susceptibility genes. Jewish people, people with a college education or beyond, people earning more than $30,000 a year, and Caucasians were more aware of the genes and of testing for these genes. Interest in being tested was similar in all groups, except for participants over 60 and those who had only an elementary-school education. Conclusions: Information concerning the breast cancer susceptibility genes has not reached the general public uniformly. A concerted effort is needed if this information is to be passed on to those people at risk.Poster presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 17–21, 1997.     

乳腺浸润性导管癌SLeX和BRCA1表达研究

目的探讨唾液酸路易斯X抗原（SLeX）和乳腺癌1号基因（BRCA1）表达与乳腺浸润性导管癌（BIDC）临床病理指标及预后的关系。 方法收集2014年5月至2015年12月手术切除的BIDC标本80例及距癌灶3 cm的癌旁乳腺组织30例,应用EliVision^TM plus免疫组织化学2步法检测SLeX和BRCA1在癌组织及癌旁乳腺组织中的表达。运用SPSS 22.0软件分析,SLeX和BRCA1阳性率、临床病理指标等计数资料用例（%）表示,组间比较进行χ²检验及相关性分析,P<0.05为差异有统计学意义。 结果癌组织SLeX和BRCA1阳性率分别为86.3%（69/80）、60.0%（48/80）,癌旁乳腺组织分别为20.0%（6/30）和100%（30/30）,差异均有统计学意义（P<0.05）。SLeX在TNM分期（T3+T4）、低分化、有淋巴结宏转移和随访5年间有复发转移患者中高表达;BRCA1在年龄>53岁、TNM分期（T3+T4）、低分化、有淋巴结宏转移和随访5年间有复发转移患者中低表达。 结论SLeX和BRCA1与BIDC的发生发展显著相关,前者表达上调和（或）后者表达下调均预示癌组织分化差、进展快、预后不良。     

Post-mastectomy surveillance of BRCA1/BRCA2 mutation carriers: Outcomes from a specialized clinic for high-risk breast cancer patients

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4–28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.