上皮性卵巢癌复发前后肿瘤组织中BRCA基因突变自身对照研究

目的:探讨上皮性卵巢癌复发前后肿瘤组织中的乳腺癌易感基因(BRCA)突变状态及其临床意义。方法:收集上海交通大学医学院附属第九人民医院妇科2008年1月至2015年12月因上皮性卵巢癌行初次肿瘤细胞减灭术及复发后再次切除肿瘤的病例10例,应用全外显子测序技术检测患者原发和复发肿瘤组织中的基因突变情况,分析复发前后BRCA基因突变状态以及与铂类化疗药物敏感性的关系。结果:10例复发性上皮性卵巢癌患者中,2例(20%)同时携带致病性BRCA胚系和体细胞突变,2例(20%)携带致病性BRCA体细胞突变。在检测到的错义突变中,6例患者携带软件预测为可能致病的错义突变,4例患者未携带任何致病或可能致病BRCA突变。致病性BRCA胚系突变患者的肿瘤突变负荷高于无BRCA胚系突变患者(5.613±0.4255/Mb vs 0.7345±0.2859/Mb,P0.0001)。携带BRCA体细胞突变的6例患者中,仅1例复发前后存在同一位点的BRCA体细胞突变,其余患者复发前后均存在不同的BRCA体细胞突变。BRCA突变主要发生在卵巢癌高发区(OCCR)以外区域,BRCA1突变主要位于exon 10,BRCA2突变主要位于exon 11。原发和复发肿瘤中均以CT碱基转换为主。患者的BRCA突变状态与铂类敏感性无明显关联。结论:复发性上皮性卵巢癌组织中BRCA突变状态可与原发肿瘤不同。在一线化疗后及疾病进展中再次监测BRCA基因突变状态,可能对复发性卵巢癌的治疗方案设计有重要意义。     

BRCA1基因c.5470＿5477del突变卵巢癌临床病理特征及预后分析

目的 探讨携带乳腺癌易感基因1(BRCA1)c.5470＿5477del突变卵巢癌的临床病理特征及预后情况。方法 采用二代测序技术,对760例于2001年1月至2020年9月在本院接受治疗、组织病理学确诊的上皮性卵巢癌患者的肿瘤组织进行BRCA1/2基因突变检测,对携带致病突变者通过唾液或血液检测确定是否为胚系突变。对BRCA1基因c.5470＿5477del突变卵巢癌诊断年龄、家族史、个人肿瘤史、病理分期、病理类型、化疗敏感性、聚腺苷二磷酸核糖聚合酶（PARP）抑制剂疗效、预后等指标进行分析。结果 760例上皮性卵巢癌患者中,214例患者携带BRCA1/2基因致病性胚系或体系突变,突变频率为28.2%(214/760)。其中BRCA1基因c.5470＿5477del突变频率最高（2.8%, 21/760）,且均为胚系突变,来自不同家系。该突变占BRCA1基因所有突变的13.5%(21/156)。BRCA1 c.5470＿5477del突变卵巢癌患者的中位发病年龄为52岁（36～67岁）。81.0%(17/21)的患者诊断年龄≥50岁,仅1例患者在40岁前发病。9例（42.9%, 9/...     

基于生物信息学途径探究卵巢上皮性癌ctDNA体细胞突变

目的:通过探索卵巢上皮性癌的体细胞变异情况,为寻找卵巢上皮性癌ctDNA的诊治靶标提供线索。方法:从癌症基因组图谱(TCGA)数据库获取卵巢上皮性癌患者体细胞突变数据、基因转录组数据,利用R软件maftools包对数据进行体细胞突变分析、突变特征分析、超突变分析、信号通路富集分析及体细胞突变基因协同和互斥分析。结果:纳入卵巢上皮性癌体细胞突变数据下载样本共411例,其中突变种类最多的为错义突变;变体类型中SNP占比最大;SNV中T>G转换最多,T>A次之;突变频率最高的基因为TP53。SNP转换与颠倒比例相当,6种转换以C>T所占百分比最高(35.19%)。富集通路分析：RTK-RAS、Hippo信号通路有突变的样本占比分别为190/411和147/411。对TOP50基因的互作关系进行分析提示绝大部分基因是共同发生(协同性)。结论:本研究借助于TCGA数据库,完成了卵巢上皮性癌体细胞突变分析,为卵巢上皮性癌发生机制研究提供了一些参考与借鉴,为促进对癌症病因学的理解及研究ctDNA提供依据。     

子宫颈鳞状细胞癌基因胚系突变特点及与临床特征的关系

目的:探讨子宫颈鳞状细胞癌(CSCC)基因胚系突变特点及与临床特征的关系。方法:选取67例CSCC患者的癌组织和癌旁组织，提取组织样本的基因组DNA、构建基因组文库和杂交捕获胚系突变基因的外显子序列进行有效PCR扩增和富集；采用二代测序(NGS)技术检测基因胚系突变情况并对其突变位点进行筛选、分类和分析。结果:57例发生胚系突变的CSCC患者组织样本共检出46种胚系突变基因及其相应的125个突变位点。46种胚系突变基因在CSCC患者中排名前10位的为FANCA、MSH2、BRCA2、BRCA1、BRIP1、TSC1、PTCH1、MSH6、CHEK2和CDKN2A,其中FANCA、BRCA2、MSH2、BRCA1及BRIP1等30种基因突变出现在2例及以上的患者中；这些突变分别发生在常染色体和X染色体上，其突变类型分别为3个移码缺失突变、112个非同义突变、4个同义突变、2个非移码缺失突变、1个终止突变和3个可变剪切位点突变。在125个突变位点中有24个(19.20%)位点发生致病性突变和101个(80.80%)位点发生非致病性突变。24个致病突变位点发生在19例CSCC患者对应的11种...     

子宫外盆腔浆液性癌的起源

子宫外盆腔浆液性癌包括卵巢浆液性癌、输卵管浆液性癌、腹膜浆液性癌。根据细胞分化程度可将卵巢浆液性癌分为低级别和高级别浆液性癌,两者临床特征、预后及分子特征完全不同,是两种不同的疾病。大量证据表明前者由卵巢的良性囊肿如浆液性囊腺瘤、内膜样囊肿等经交界性肿瘤逐步发展而来,而后者起源不明确。传统观点认为高级别浆液性癌起源于卵巢上皮,但对因携带遗传性乳腺癌-卵巢癌综合征易感基因(BRCA)突变行预防性输卵管卵巢切除术的患者手术标本行病理检查,可发现其输卵管伞端存在上皮内癌灶,可能为卵巢高级别浆液性癌的前驱病灶。输卵管浆液性癌及腹膜浆液性癌患者的临床及分子特征与卵巢高级别浆液性癌相似,且输卵管伞端也可见上皮内癌灶,故卵巢高级别浆液性癌、输卵管浆液性癌、腹膜浆液性癌可能均起源于输卵管伞端的上皮内癌灶。     

卵巢上皮性癌组织中p15、p16基因突变及其临床意义

ｐ15、ｐ16基因是近年来发现和分离的两个抑癌基因。研究表明,ｐ15、ｐ16基因突变与人类肿瘤的发生有关,在多种原发性肿瘤及其肿瘤细胞系中均存在ｐ15、ｐ16基因纯合性缺失与点突变[1]。本研究旨在通过检测卵巢上皮性癌(ＯＥＣ)中ｐ15、ｐ16基因纯合性缺失与点突变,探讨其在ＯＥＣ发生、发展中的作用,并评价其可否作为肿瘤标记物应用于ＯＥＣ的诊断、监测及预后的判断。一、资料与方法1.研究对象:43例ＯＥＣ、11例卵巢良性上皮性瘤及4例卵巢交界性上皮性瘤取自山东医科大学附属医院、山东省立医院及解放军第九○医院妇产科1995～1997年住院…     

卵巢上皮性癌中肌切蛋白的表达及其临床意义

目的:探讨肌切蛋白(Scinderin)在卵巢上皮性癌中的表达及其临床意义.方法:运用实时荧光定量聚合酶链式反应(PCR)法和蛋白质印迹(Western blot)法分别检测34例卵巢上皮性癌、21例卵巢良性肿瘤和20例正常卵巢组织中肌切蛋白mRNA和蛋白的表达情况,并进行临床资料统计,分析肌切蛋白与卵巢上皮性癌临床病理参数间的关系.结果:卵巢上皮性癌组中肌切蛋白mRNA及蛋白表达量均显著高于良性卵巢肿瘤组和正常卵巢组(P＜0.01),而在正常卵巢组与良性卵巢肿瘤组中,肌切蛋白mRNA及蛋白表达量差异无统计学意义(P＞0.05).肌切蛋白mRNA和蛋白表达与卵巢上皮性癌病理分级、淋巴结转移有关(P ＜0.01;P＜0.05),而与患者年龄、肿瘤临床分期无相关性(P＞0.05).结论:肌切蛋白在卵巢上皮性癌中表达上调,且在低分化卵巢上皮性癌中表达高于中-高分化卵巢上皮性癌,有淋巴结转移者高于无淋巴结转移者,提示肌切蛋白与卵巢上皮性癌患者的不良预后相关,可作为判断卵巢上皮性癌预后的生物学标志物.     

卵巢上皮性癌中p53基因缺失与HER-2基因扩增及其临床意义

目的:检测卵巢上皮性癌中17号染色体上野生型p53基因缺失与HER-2基因的扩增情况并探讨其临床意义。方法:分别以不同颜色荧光标记的p53、HER-2基因和17号染色体着丝粒为双色探针组,应用间期双色荧光原位杂交(FISH)技术检测54例卵巢上皮性癌间期细胞核中p53基因、HER-2基因和17号染色体的拷贝数及其相对比例,以确定其缺失或扩增,并统计分析其临床意义。结果:54例卵巢上皮性癌中p53基因缺失38例(70.4%);HER-2基因扩增14例(25.9%);17号染色体多倍体有35例(64.8%)。p53基因缺失与17号染色体多倍体呈正相关(χ2=12.116,P<0.001),与HER-2基因的扩增无关(χ2=0.00,P=1.00)。p53基因缺失与卵巢上皮性癌患者肿瘤分期及体积大小无关(P>0.05),而与血CA125水平及淋巴结转移有关(P<0.05);术后2年存活率p53基因缺失患者显著低于无缺失患者(81.3%,χ2=4.186,P=0.047)。结论:p53基因高频缺失和HER-2基因扩增,可能与部分卵巢上皮性癌的发生发展有关。     

上皮性卵巢癌中PTEN突变分析

目的 :探讨抑癌基因PTEN与上皮性卵巢癌的发生发展之间的关系。方法 :收集上皮性卵巢癌 6 0例 (浆液性 4 7例 ,粘液性 13例 )和良性上皮性卵巢肿瘤 10例及正常卵巢组织 5例 ,提取组织DNA后用PCR SSCP方法检测PTEN基因的第 5、8外显子的突变。结果 :3例 (2例浆液性腺癌、1例粘液性腺癌 )突变 ,并经DNA测序结果证实。结论 :在上皮性卵巢癌的发生发展过程中PTEN突变可能起作用 ,但不能除外该基因有突变以外的其他异常改变参与了肿瘤的发生。     

c-kit基因及其靶体SCF在卵巢上皮性肿瘤中的表达

目的:研究c-kit基因及其靶体干细胞因子(stem cell factor,SCF)在卵巢上皮性肿瘤的表达及临床意义,探讨其在卵巢上皮性癌发生发展中的可能作用。方法:免疫组化SP法测定10例正常卵巢组织,20例卵巢良性上皮性肿瘤,16例卵巢交界性上皮性肿瘤,58例卵巢上皮性癌标本中c-kit、SCF蛋白的表达。结果:(1)卵巢上皮性癌中c-kit蛋白阳性表达率为63.79%,明显高于正常卵巢组织(0%)及卵巢良性上皮性肿瘤(10.00%),差异有显著性(P<0.01);卵巢交界性上皮性肿瘤中c-kit阳性表达率为43.75%(7/16),也高于正常卵巢组织及卵巢良性上皮性肿瘤,差异有显著性(P<0.05);(2)卵巢上皮性癌中,低分化组的c-kit蛋白阳性表达率高于高、中分化组(P<0.05),c-kit蛋白的阳性表达率随FIGO分期的进展及淋巴结转移而升高(P<0.05);(3)c-kit阳性患者的预后比c-kit阴性患者差(P<0.05);(4)SCF在正常卵巢上皮、卵巢良性上皮性肿瘤、卵巢交界性上皮性肿瘤、卵巢上皮性癌中的阳性表达率分别为30.00%、35.00%、62.50%和74.14%,卵巢上皮性癌的阳性表达率显著高于正常卵巢组织及卵巢良性上皮性肿瘤(均P<0.01)。卵巢癌低分化组SCF的阳性表达率显著高于高、中分化组(P<0.05)。且随FIGO分期的进展及淋巴结转移而升高(P<0.05);(5)c-kit与SCF表达具有明显相关性(r=0.302,P<0.05)。结论:(1)c-kit、SCF表达异常可能在卵巢上皮性癌的发生发展中起重要作用;(2)c-kit、SCF在卵巢上皮性癌中的表达具有相关性,SCF作为c-kit的配体,可促使c-kit活化,两者具有协同作用(3)c-kit蛋白表达与卵巢上皮性癌患者的预后有关,可作为判断卵巢上皮性癌患者预后的指标之一。     

Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study

OBJECTIVES: The aim of the study was to determine the prevalence of BRCA1 and BRCA2 germline mutations among ovarian cancer patients ascertained to have a family history of ovarian cancer. METHODS: Ovarian cancer patients were eligible if they had a family history of cancer that met any one of the following criteria: (1) a first-degree relative with ovarian cancer; (2) a second-degree relative with ovarian cancer plus a first-degree relative with breast cancer (diagnosed younger than 50 years of age); or (3) a first- and a second-degree relative with breast cancer (diagnosed younger than 50 years of age). The entire coding sequence of BRCA1 and exon 11 of BRCA2 were screened for germline alterations by single-strand conformation polymorphism analysis. RESULTS: Of 26 eligible patients screened for mutations, 12 had deleterious alterations, 8 in BRCA1 and 4 in BRCA2. A correlation was noted between the presence of a BRCA1 mutation and the strength of family history of breast ovarian cancer, with the likelihood of a mutation increasing with the number of affected relatives (P = 0.0002). No association was detected between the location of mutations in BRCA1 and the ratio of ovarian cancer cases relative to breast cancer (P = 0.28). CONCLUSIONS: Mutations in BRCA1 or BRCA2 are present in about 50% of ovarian cancer patients with at least one first-degree relative with disease, and in 70% of patients with two or more relatives with ovarian cancer.     

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer

Background

The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.

Methods

We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).

Results

Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.

Conclusions

BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.     

BRCA1 Germline Mutations and Polymorphisms in a Clinic-Based Series of Ovarian Cancer Cases: A Gynecologic Oncology Group Study

OBJECTIVE: The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. METHOD: Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. RESULTS: Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. CONCLUSION: In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing.     

Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry.

Studies of the histopathology of ovarian cancer arising in patients with germline mutations in BRCA1 or BRCA2 have shown inconsistent findings. We analyzed the large number of tumors from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry for correlations between histopathology and BRCA mutation status. Histopathology slides and reports were reviewed for histology, grade, and stage for cancers of the ovary or peritoneum in 220 women from 126 Gilda Radner Familial Ovarian Cancer Registry families. At least one affected member of each family was analyzed for mutations in the BRCA1 and BRCA2 genes, and tumors from mutation-positive families were compared with those from mutation-negative families. Of 70 patients from 38 BRCA1-positive families, 69 had epithelial ovarian carcinoma and one had a dysgerminoma. Fifteen of 16 patients from nine BRCA2-positive families had epithelial ovarian cancer, and one had a primary peritoneal cancer. Of 134 patients from 79 BRCA-negative families, 118 had epithelial ovarian carcinoma, 11 had ovarian borderline tumors, three had nonepithelial tumors, and two had primary peritoneal carcinoma. There were fewer grade 1 (p < 0.001) and stage I (p = 0.005) cancers in patients from BRCA-positive families than in patients from BRCA-negative families. Neither mucinous nor borderline tumors were found in the BRCA-positive families. In conclusion, ovarian cancers arising in women from BRCA-positive families are more likely to be high-grade and have extraovarian spread than tumors arising in women from BRCA-negative families. Borderline and mucinous tumors do not appear to be part of the phenotype of families with germline mutations in the BRCA genes.     

Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in israel

OBJECTIVE: The objective was to evaluate the prevalence of BRCA1/2 mutations in selected categories of ovarian cancer patients in Israel. METHODS: Blood samples and specimens of ovarian tumors were obtained in the course of a national case control study of women with ovarian cancer in Israel. Eight hundred ninety-six patients with epithelial ovarian cancer, 40 cases with nonepithelial ovarian cancer, and 68 with primary peritoneal cancer were tested for the BRCA mutations. Analysis of the three common BRCA mutations in Israel (185delAG, 5382insC in BRCA1, and 6174delT in BRCA2) was done using a multiplex polymerase chain reaction assay. A multivariate logistic regression model was used to assess the association of mutation carrier status and other factors (age, origin, family history, and clinical variables). RESULTS: Of the 779 invasive epithelial ovarian cancer cases, 29.4% were mutation carriers. The prevalence of the mutations was higher among women below age 60 and in more advanced cases. The prevalence was low in mucinous tumors. There was almost a twofold excess of mutations among women with positive family history (45.7%), but still 26.5% of the family history negative cases were carriers. As expected, we found a higher rate of mutation carriers among the Ashkenazi group (34.2%) and 55% among Ashkenazi women with positive family history. No subjects born in North Africa were mutation positive. CONCLUSION: BRCA mutations are strongly associated with ovarian cancer and they are present in variable rates in distinct age, ethnic, and histopathologic categories.     

Mutational analysis of TP53 and p21 in familial and sporadic ovarian cancer in Japan

OBJECTIVE: To investigate whether somatic mutations in cell cycle checkpoint genes, TP53 and p21, are involved in the development of ovarian cancer with or without BRCA1 germline mutation. METHODS: We analyzed somatic genetic alterations of TP53 and p21 in 46 ovarian cancer patients with BRCA1 germline mutations and 93 sporadic patients, using direct sequencing for the entire coding sequences in TP53 and p21. RESULTS: TP53 somatic mutations were detected in 25 of the 46 BRCA1 cases and 40 of the 93 sporadic cases (54.3% vs. 43.0%). In contrast, p21 somatic mutations were detected in 1 of the 46 BRCA1 cases and 2 of the 93 sporadic cases (2.2% vs. 2.2%). TP53 mutations in sporadic cases more frequently occurred in exons 6-11 than those in cases with germline BRCA1 mutations (84.4% vs. 56.3%: P = 0.013). The proportion of sporadic cases with TP53 mutations in non-serous tumors (e.g. endometrioid, clear cell, or mucinous) was significantly lower than that in serous tumors (18.5% vs. 53.0%: P = 0.0038). However, there was no significant difference between the proportion of BRCA1 cases with TP53 mutation in non-serous and in serous tumors (37.5% vs. 57.9%). CONCLUSIONS: Our results suggest that somatic mutation of TP53 plays less of a role in the carcinogenesis of sporadic non-serous tumors than in that of sporadic serous tumors or BRCA1-related tumors. Furthermore, p21 somatic mutation appears to be less involved in the development of ovarian cancer than TP53 somatic mutation.     

The current landscape of molecular profiling in the treatment of epithelial ovarian cancer

Advances in next generation sequencing have allowed for rapid and economical germline and tumor genomic profiling. Targeted therapies based on molecular tumor profiling are now integrated into treatment guidelines for many solid tumors. In epithelial ovarian cancer, 50% of tumors possess damaging mutations in homologous recombination repair genes (aka homologous recombination deficiency or HRD) which includes the BRCA genes. Deleterious BRCA mutations and HRD have recently emerged as predictive biomarkers for the use of PARP inhibitors in ovarian cancer. Every patient with ovarian cancer must be referred for genetic counseling and germline testing for BRCA mutations. Multigene panel genetic testing may be more informative and cost-effective than limited testing of cancer susceptibility genes. Patients without a germline deleterious BRCA mutation must be assessed for a somatic BRCA mutation. Assays for HRD may help guide treatment options in women who do not have a BRCA mutation. Currently, all patients with a germline or somatic BRCA mutation should be offered upfront maintenance therapy with a PARP inhibitor. During May 2020, options for maintenance therapy with a PARP inhibitor were expanded to patients with HRD and HR-proficient tumors.     

BRCA1 germline mutations in women with uterine serous papillary carcinoma

OBJECTIVE: To determine the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma. METHODS: We screened DNA from 12 women with uterine serous papillary carcinoma for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382insC, BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity at the appropriate loci. RESULTS: Nine women were of Jewish Ashkenazi origin and three were non-Ashkenazi. Two of nine Ashkenazi women were carriers of germline mutations: one 185delAG mutation and one 5382insC mutation. Five women had histories of breast carcinoma before diagnosis of uterine serous papillary carcinoma. Family histories of seven women had at least one first-degree relative with malignant disease. Of those, four had at least one first-degree relative with breast, ovarian, or colon carcinoma. Both carriers had strong family histories of breast-ovarian carcinoma. Loss of heterozygosity analysis found loss of the wild-type BRCA1 allele in the primary uterine tumors. CONCLUSION: BRCA1 germline mutations were observed in two of nine of the women in this series. The loss of heterozygosity in the tumor tissue of the carriers, coupled with the high frequency of family and patient histories of breast or ovarian malignancies, suggest that uterine serous papillary carcinoma might be a manifestation of familial breast-ovarian cancer.     

Primary ovarian dysgerminoma in a patient with a germline BRCA1 mutation.

Germline mutations in the BRCA1 tumor suppressor gene are associated with increased risk for the development of ovarian cancer. All such cancers thus far reported have been of the epithelial histologic type. We identified an ovarian dysgerminoma in a 16-year-old woman (proband) with a family history of ovarian cancer during a review of histopathologic characteristics of ovarian cancers from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Mutation analysis of DNA from this patient's peripheral blood leukocytes revealed a germline BRCA1 mutation (3312insG). The mutation was also present in the mother with breast cancer, a maternal aunt and a distant cousin with ovarian cancer, and a maternal grandfather and an uncle with skin cancer. The development of the proband's dysgerminoma may be unrelated to her germline BRCA1 mutation. Alternatively, such dysgerminomas may be caused by BRCA1 mutations, but occur so infrequently compared with epithelial cancers that they are seldom identified. Analysis of a larger series of ovarian germ cell tumors may resolve this question.     

BRCA germline mutations in Jewish women with uterine serous papillary carcinoma

OBJECTIVE: Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC. METHODS: We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382 insC,BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci. RESULTS: Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast-ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined. CONCLUSIONS: Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast-ovarian cancer in Ashkenazi Jewish patients.