Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer

Loss of heterozygosity (LOH) in loci of the 17q21 and 13q1213 regions can collaborate in the inactivation of BRCA1, BRCA2, and possibly other genes implicated in the pathogenesis of breast carcinomas. We investigate allelic losses in microsatellites of the BRCA1 and BRCA2 regions, and their correlations with seven pathologic parameters in 140 breast carcinomas. Those cases showing LOH in the region of the RB gene, 13q14, were excluded from the study. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 17q21 region (D17S856, D17S855, D17S1323, and D17S1327) and four markers of the 13q1213 region (D13S290, D13S260, D13S310, and D13S267). LOH in the BRCA1 region was found in 47% of tumors, correlating significantly with estrogen receptor content (p = 0.025), progesterone receptors (p = 0.004), higher grade (p = 0.0008), peritumoral vessel invasion (p = 0.001), and lymph node metastases (p = 0.002). When we excluded the cases with LOH in the BRCA2 region and those not informative for it, the significance disappeared. In the BRCA2 region, a rate of LOH of 51% was found; it correlated significantly with estrogen receptor content (p = 0.002), progesterone receptors (p =0.03), peritumoral vessel invasion (p = 0.005), higher grade (p =0.002), and lymph node metastases (p = 0.001). When cases with BRCA1 losses and those not informative were excluded, again the significance disappeared. Concomitant losses in the BRCA1 and BRCA2 regions were found in 32% of cases, correlating significantly with lymph node metastases (p = 0.0002), estrogen receptor content (p = 0.003), progesterone receptors (p = 0.001), histologic grade (p =0.01), and peritumoral vessel invasion (p = 0.0004). These results suggest that concomitant losses in both regions could have a functional effect, influencing the presence of a poor tumor pathophenotype in breast carcinomas.     

Baseline and post prophylactic tubal–ovarian surgery CA125 levels in BRCA1 and BRCA2 mutation carriers

The aim of this study was to determine whether BRCA1 and BRCA2 mutation carriers have different baseline CA125 levels compared with non-carriers, and whether a significant difference in pre- and post-operative CA125 levels exists in BRCA mutation carriers undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). The study also considered whether CA125 measurements should continue in unaffected BRCA mutation carriers after RRBSO. 383 Eligible women were identified through retrospective review of the BRCA Carrier Clinic at The Royal Marsden NHS Foundation Trust, London, UK. These women all had CA125 levels measured as they were either a carrier or at risk of a BRCA1 or BRCA2 mutation. Of these, 76 went on to have a negative predictive test for their familial mutation and so are classed as ‘non-carriers’. 133 BRCA1 and 87 BRCA2 carriers had RRBSO, with a further 26 BRCA1 carriers, 28 BRCA2 carriers and one non-carrier developing ovarian cancer. The remaining 21 BRCA1 and 28 BRCA2 carriers did not have RRBSO or develop ovarian cancer in the time of study follow-up. CA125 levels were measured as surveillance or as part of pre-RRBSO care. CA125 measurement post-RRBSO was continued in 48 BRCA1 and 40 BRCA2 carriers. In 154 BRCA1 mutation carriers, the median baseline (i.e. before RRBSO and with no clinical signs of ovarian cancer) CA125 level was 9.0 U/ml (range 2–78) and was 10.0 U/ml (range 1–43) in 115 BRCA2 mutation carriers. When compared with the 75 non-carriers (median baseline CA125 10.0 U/ml; range 2–52), there was no significant difference between the BRCA1, BRCA2 and non-carrier groups. There was a significant reduction in CA125 from pre- to post-RRBSO in 48 BRCA1 carriers (p = 0.04) but no significant difference in 40 BRCA2 mutation carriers (p = 0.5). Out of a total of 220 mutation carriers who underwent RRBSO, two had an incidental ovarian cancer found on histopathology and another developed primary peritoneal cancer during the follow-up period. Our study is the first to compare initial serum CA125 levels in BRCA1 and BRCA2 mutation carriers with those of non-carriers. Our study found no significant difference between the three groups. A drop in CA125 levels after RRBSO in BRCA1 carriers supports the finding of earlier studies, but differed in that the fall was not seen in BRCA2 carriers. The finding of only one case of post-operative peritoneal cancer in 220 carriers undergoing RRBSO supports the discontinuation of post-RRBSO serum CA125 monitoring in BRCA mutation carriers.     

Are BRCA1- and BRCA2-related breast cancers associated with increased mortality?

There has been contradictory evidence as to whether BRCA1 associated breast cancers have a poorer prognosis than non-BRCA1 cancers. In this issue of Breast Cancer Research Robson and colleagues provide further evidence for poorer survival in BRCA1 carriers and show that it could be attributed to failure to treat small node-negative grade 3 breast cancers with chemotherapy. There still remains little evidence for a survival difference for BRCA2 related breast cancers. Although the high contralateral breast cancer risk is confirmed by this study there is no real evidence for an increase in ipsilateral recurrence or new primary breast cancers in mutation carriers up to the 10-year point.     

Are the hereditary forms of BRCA1 and BRCA2 breast cancer sensitive to estrogens?

There is emerging evidence from clinical and experimental data that familial breast cancers, including BRCA1 and BRCA2 related forms, could be in fact estrogen-sensitive. Interactions between BRCA1 gene expression and estrogens have been reported. On one hand, BRCA1 expression could be induced by estradiol in experimental models. On the other hand, recent studies indicate that BRCA 1 interacts with and regulates the activity of estrogen receptor ERalpha. Endogenous or exogenous estrogens, such as oral contraceptive, may also increase the risk of breast cancer in BRCA1 mutation carriers in clinical studies. Conversely, prophylactic oophorectomy and anti-estrogens may decrease the risk of familial breast cancer. Prospective studies are thus required to estimate the potential benefits of estrogen suppression therapies for prevention or adjuvant treatment of familial breast cancer. Oral contraception and hormonal replacement therapy after menopause should be used with caution in BRCA1 or BRCA2 mutation carriers.     

MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi–Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41–10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69–2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.     

A gene-environment interaction between occupation and BRCA1/BRCA2 mutations in male breast cancer?

The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.     

BRCA1和BRCA2的始祖突变

BRCA1和BRCA2的突变与乳腺癌和卵巢癌的发生密切相关。BRCA1和BRCA2的始祖突变多种多样,而且在不同民族、不同地域的人口中突变类型和频率不尽相同。在特定的人口中,始祖突变由于存在始祖效应,其发生率较高。与昂贵的全基因扫描相比,始祖突变检测更加方便、经济和易于普及,能为相关癌症的预防和治疗提供信息。     

Inherited predisposition to breast cancer: after the BRCA1 and BRCA2 genes,what next?

Germline mutations of the breast cancer predisposing known genes, BRCA1 and BRCA2, with an autosomal dominant transmission explain only a part of the familial aggregation of breast cancer. Mainly involved in families with cases of ovarian cancer or male breast cancer, they account for a small proportion of families where only female breast cancer cases are observed. A third predisposing gene, called BRCA3, has been sought for a long time but without success. Recently, genetic epidemiology studies have shown evidence for non-mendelian inheritance. The familial residual risk non due to BRCA1 or BRCA2 genes could be explain by a polygenic model, corresponding to the multiplicative effects of several genes, more frequent in population but conferring moderate risks of cancer. The identification of these low penetrance genes is the challenge over the next years. We present here a focusing of recent knowledge on breast cancer predisposing genes, the perspectives of research and their implications in the practice of genetic counselling.     

散发性乳腺癌BRCA1和BRCA2基因突变分析

目的探讨散发性乳腺癌患者BRCA1及BRCA2基因突变与健康人的差异。方法应用聚合酶链反应-单链构象多态性（PCR-SSCP）分析方法,对83例散发性乳腺癌患者（乳腺癌组）与86例健康人（健康对照组）的血液标本,针对BRCA1和BRCA2基因,选择4个突变发生率较高的外显子[BRCA1中的第5、11（11A、11B）、18外显子,BRCA2中的第11外显子]共5对引物进行突变检测,并应用限制性片段长度多态性（RFLP）方法对具有单核苷酸多态的碱基位点作单核苷酸多态性定性分析。成组设计的定性资料比较采用χ^2检验。结果部分散发性乳腺癌患者和健康人BRCA1基因第5外显子的cDNA 273和287（C→G和A→T）,第11外显子的2430、2532、2630、2685、3191、3232和3667、3876（T→C、T→C、T→G、T→C→G、A→G、A→G和C→A）以及第18外显子的5206和5214（T→A和C→T）碱基位点处存在单个碱基的变化,散发性乳腺癌患者的BRCA1基因突变率高于健康人（14．5％比2．3％,P〈0．05）;应用RFLP方法证实cDNA 2430、2630（T→C、T→G）碱基位点的变化为单核苷酸多态（SNP）;散发性乳腺癌患者与健康人2430（T→C）碱基位点等位基因频数分布不相同,但差异无统计学意义（P〉0．05）。结论散发性乳腺癌患者BRCA1基因突变较常见,而BRCA2的突变十分罕见。     

乳腺癌与BRCA

ＢＲＣＡ１和ＢＲＣＡ２基因的发现为乳腺癌的早期诊断和治疗及提高生存率和生存质量带来了希望。其在乳腺癌中有较高的突变率和特异性。本文综述乳腺癌的基因筛查及与ＢＲＣＡ之间的关系。     

华东地区乳腺癌散发病例BRCA1、BRCA2基因突变

目的：探讨华东地区乳腺癌散发病例BRCA1及BRCA2基因突变情况。方法：应用PCR-SSCP-Sequencing方法,对复旦大学附属肿瘤医院79例随机乳腺癌患者的癌组织及癌旁正常乳腺组织的标本进行BRCA1和BRCA2部分基因的突变检测,共6个外显子（BRCA1中的第2、11、22外显子,BRCA2中的第9,14,22外显子）23对引物。结果：发现在BRCA1和cDNA 2430碱基处存在一个T→C的单个碱基的变化,应用RFLP方法在人群中证实为一单核苷酸多态。此SNP的分布在病例及对照中等位基因频率存在差异,但并未达到显著性水平。结论：提示华东地区人群的乳腺癌群体中的BRCA1及BRCA2的突变十分罕见。     

乳腺癌BRCA1、BRCA2基因突变及其临床应用

乳腺癌的发生与遗传因素密切相关.研究表明,乳腺癌易感基因(BRCA)1、2在乳腺癌的发生、发展过程中具有重要作用,针对BRCA基因突变的研究对乳腺癌的预防、诊断及治疗具有重要意义.     

苏州地区乳腺癌患者BRCA1和BRCA2基因突变的分析

目的 探讨中国苏州地区乳腺癌患者乳腺癌易感基因1(BRCA1)和乳腺癌易感基因2(BRCA2)基因的突变位点及携带情况，并对携带致病突变基因患者的家系成员进行基因筛查和风险管理。方法 收集2018年7月至2021年10月确诊的85例乳腺癌患者，其中早发性乳腺癌40例，家族性乳腺癌36例，三阴性乳腺癌35例。采用高通量测序技术，对患者外周血中BRCA1和BRCA2基因的外显子及其部分内含子序列进行检测，将检测到的致病突变与ClinVar数据库进行对照，确定是否为新发现的致病突变。通过对家系先证者进行遗传咨询和肿瘤易感基因检测，进一步对携带致病基因患者的健康家系成员进行BRCA基因突变筛查。结果 85例乳腺癌患者中BRCA1和BRCA2的总致病突变率为21.2%(18/85),其中BRCA1致病突变率为11.8%(10/85), BRCA2致病突变率为9.4%(8/85)。在18例致病性突变患者中发现3个新发位点，分别为BRCA1基因c.1559dupA,BRCA2基因c.8939-8941delinsT和BRCA2基因c.3677-3678insATGAAAT。进一步对携带BRCA1/B...     

Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case–control study

Background  Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer. Many patients are interested in the possibility of an adverse effect of fertility treatment on breast cancer risk. It is important to evaluate whether or not infertility per se or exposure to fertility medications increase the risk of breast cancer in genetically predisposed women. Methods  We conducted a matched case–control study of 1,380 pairs of women with a BRCA1 or BRCA2 mutation to determine if a history of infertility, the use of fertility medications, or undergoing in vitro fertilization (IVF) were associated with and increased the risk of breast cancer. Results  Sixteen percent of the study subjects reported having experienced a fertility problem and 4% had used a fertility medication. Women who had used a fertility medication were not at significantly increased risk of breast cancer (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.81–1.82) compared to non-users. Furthermore, there was no risk associated with a history of use of a fertility medication when the subjects were stratified by parity: (OR = 1.29; 95% CI = 0.83–2.01 for nulliparous women and OR = 0.81; 95% CI = 0.30–2.22 for parous women). Conclusions  The results of this study suggest that the use of fertility medications does not adversely affect the risk of breast cancer among BRCA mutation carriers. Given the small sizes of the exposed subgroups, these findings should be interpreted with caution and confirmatory studies are required. Other Members of the Hereditary Breast Cancer Clinical Study Group: D. Horsman, British Columbia Cancer Agency, Vancouver, BC, Canada; B. Rosen, Familial Ovarian Cancer Clinic, Princess Margaret Hospital, Toronto, ON, Canada; C. Isaacs, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA; S. Domchek, Departments of Hematology and Oncology, University of Pennsylvania, USA; R. Gershoni-Baruch, Institute of Genetics, Rambam Medical Center, Haifa, Israel; A. Eisen, Cancer Risk Assessment Clinic, Juravinksi Cancer Centre (Hamilton Regional Cancer Centre), Hamilton, ON, Canada; O. I. Olopade, Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL, USA; E. Friedman, The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; H. M. Saal, Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, OH, USA; S. L. Neuhausen, Epidemiology Division, Department of Medicine, University of California, Irvine, USA; M. Daly, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA; B. Karlan and R. N. Kurz, Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA; C. Bellati, Section of Genetics, University of Turin, Turin; Italy C. Eng, Chair of Genomic Medicine Institute at the Cleveland Clinic Foundation Cleveland, Cleveland, OH, USA; K. Sweet, Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus OH, USA; T. Wagner, Department of Gynecology, Division of Senology, Medical University of Vienna and Private Trust for Breast Health, Austria; G. Rennert, National Cancer Control Center, Carmel Medical Center, Haifa, Israel; D. Provencher and C. Maugard, University of Montreal, Quebec, Canada; J. Garber, Dana Farber Cancer Center, W. McKinnon and M. Wood, University of Vermont; D. Gilchrist, University of Alberta; M. Osborne, Strang Cancer Prevention Centre, New York, NY, USA; J. McLennan, University of San Francisco, California, USA; S. Merajver, University of Michigan Comprehensive Cancer Cente;, B. Pasche and T. Fallen, Northwestern University Cancer Genetics Program, Chicago, Illinois, USA; E. Lemire, Division of Medical Genetics, Royal University Hospital and the University of Saskatchewan, Saskatoon, Canada; A. Chudley, Children’s Hospital, Winnipeg, Manitoba, Canada; J. Weitzel, Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California, USA; W. S. Meschino, North York General, North York, ON, Canada; D. Rayson, Queen Elizabeth Health Sciences Centre, Halifax, Nova Scotia, Canada; G. Evans, Regional Genetics Service, St. Mary’s Hospital, Manchester, UK; D. Agnese, Division of Human Genetics, The Ohio State University; and H. Olsson, Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden.