CLINICAL GENETIC STUDIES OF FAMILIAL & HEREDITARY CANCER

临床遗传学分会（CGB）将癌症遗传学的分子和临床观察纳入跨学科的方法，包括流行病学，临床，遗传学，行为学，统计学和实验室方法，以确定易感基因在癌症病因学中的作用。本研究项目的主要目标是将分子遗传学的最新进展转化为癌症遗传风险增加的人群的循证管理策略。核心研究策略依赖于对癌症易发家庭的个体成员进行详细而细致的评估。CGB承担的第一个重大临床研究项目代表了DCEG长期致力于遗传性乳腺癌和卵巢癌（HBOC）研究的下一阶段。遗传流行病学分部对BRCA1或BRCA2突变的26个HBOC家族（包括216名检测或推断为BRCA1/2突变阳性的个体和392名检测为突变阴性的家庭成员）的持续随访和下一代分析研究的责任已转移到CGB。对于这些家庭，首要任务是为感兴趣的家庭成员提供BRCA1/2突变的临床预测性基因检测。同时，我们将为这些人制定一个精心设计的研究方案。该项目将解决与乳腺癌筛查、早期诊断、与遗传风险评估和测试过程相关的行为、教育和社会心理动力学、作为遗传性乳腺癌风险因素的内源性激素以及与使用他莫昔芬作为乳腺癌化学预防策略相关的家庭成员决策相关的问题。与这项研究有关的概念和协议目前正在制定中。该研究的第一个组成部分是一项试点研究，评估乳房x光检查、核磁共振成像和PET成像作为乳腺癌遗传风险增加的妇女的筛查工具。该方案已通过DCEG科学审查程序，并已获得临床中心IRB的批准，预计将在未来几个月内招募首批受试者。该项目还将评估月经周期时间对乳腺MRI成像特征的影响，并为我们提供一个评估乳腺导管灌洗的机会，这是一种获得乳腺导管上皮细胞的新技术，作为这种情况下的早期诊断工具，以及作为分子遗传学研究生物材料的潜在来源。1994 - 1995年间，一项关于BRCA1/2始祖突变流行率的研究正在对1000名德系犹太人前列腺癌患者进行研究。对这些样本的基因检测预计将在年底前完成。与病理学/DCS实验室合作，计划对BRCA1/2突变相关的前列腺癌与与此类突变无关的癌症的组织病理学进行系统比较。我们还将对brca1,2相关前列腺癌进行杂合性缺失研究。本研究的目的是解决目前关于前列腺癌是否是brca1,2综合征的特征之一的不确定性。如果答案是肯定的，这将为在HBOC突变携带者家族中进行前列腺癌筛查和预防研究提供依据。在管理携带BRCA1/2基因突变的女性的许多紧迫的临床问题中，预防性卵巢切除术作为一种降低风险的策略的适当作用。与妇科肿瘤学组（GOG）和卵巢癌早期检测资源网络（EDRN）的研究人员合作，正在计划对选择接受预防性卵巢切除术的有遗传风险的妇女进行全国性的前瞻性随访研究。这将使我们能够解决以下问题：(a)在预防性卵巢切除术时临床隐匿性卵巢癌的患病率是多少？(b)有遗传风险的女性卵巢中是否存在可识别的前驱病变？(c)术后原发性腹膜癌和乳腺癌的发生率是多少？(d)这种手术对选择手术的妇女的生活质量有何影响？与brca1,2相关的卵巢癌的另一个主要问题是缺乏对这种通常致命的疾病的有效筛查措施。计划于2001年4月举行一次讲习班，以解决这一缺陷，并试图确定值得进一步临床评价的新的筛查策略。我们还在与一名校外调查员协商合作，该调查员收集了大量基于人群的卵巢癌病例和对照。目的是确定本研究受试者的BRCA1/2突变状态，提供更准确的可归因于这种基因改变的卵巢癌比例的估计，并允许详细分析突变状态和口服避孕药暴露与卵巢癌风险的相互作用。至关重要的是，要确定具有卵巢癌遗传风险的妇女是否能从口服避孕药中获得与一般人群中有文献记载的妇女相同的保护益处。我们已经启动了一个多学科研究项目，该项目将重点研究易导致骨髓衰竭、急性白血病和成年幸存者实体瘤的遗传性儿科疾病。范可尼贫血是这些疾病的原型，这些疾病还包括先天性角化不良症、Diamond-Blackfan综合征和Schwachman-Diamond综合征。这些罕见的疾病将被用作研究人类癌变机制的模型。这一机会是由招募一位杰出的临床研究者（Blanche P. Alter博士）创造的，他在这些疾病患者的临床管理和实验室评估方面都享有国际声誉。随着CGB工作人员数量的增加，预计将有更多的研究较少的家族性/遗传性癌症易感性疾病被选择进行研究。第一个是家族性睾丸癌，多年来，DCEG一直对这一实体断断续续地感兴趣。最近睾丸癌易感基因在X染色体上的定位，加上环境流行病学分部的流行病学同事即将启动一项新的、大型睾丸癌病例对照研究，导致CGB致力于一项重大的家族性睾丸癌项目。我们已经加入了国际睾丸癌连锁联盟，并为他们的基因定位/克隆工作做出了贡献，这些DNA来自于几年前在NCI研究过的一系列家族。我们正在谈判，以在一个中心审查睾丸癌病理和分析发生的癌症以外的生殖细胞肿瘤在财团家族集。一种积累新的睾丸癌家族的机制已经发展起来，我们期望从他们那里获得DNA用于定位克隆目的，并邀请选定的家族到NIH临床中心进行更详细的、病因导向的、临床/遗传/实验室研究，这些研究在历史上已经被DCEG研究者做得很好。同一家族的不同成员同时患乳腺癌和结肠癌的几率似乎比已知的遗传性癌症综合症更大。我们正计划对患有双原发乳腺癌和结肠癌的妇女进行一项家庭/基因研究，以努力阐明这种关联。将寻找尚未确定的癌症易感基因的证据。在其他可能的研究列表中名列前茅的是家族性造血和淋巴增生性疾病的系统调查，特别关注患有多种不同类型癌症的家庭。这将建立在先前对家族性霍奇金淋巴瘤和急性白血病的DCEG研究，以及目前对家族性非霍奇金淋巴瘤、慢性淋巴细胞白血病和Waldenstrom巨球蛋白血症的研究基础上。根据需要，CGB还将在分析作为DCEG其他地方同事正在进行的分析流行病学研究的一部分收集的家族史数据方面发挥作用。第一个这样的项目需要评估癌症家族史和西方化水平作为癌症风险因素，这是一项基于人群的亚裔美国女性乳腺癌病例对照研究。这是通过与流行病学和生物统计学项目以及遗传流行病学处的研究人员合作完成的。

The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). Responsibility for the ongoing follow-up, and for the next generation of analytic studies, of the Genetic Epidemiology Branch's cohort of 26 HBOC families with mutations in either BRCA1 or BRCA2 (including 216 individuals tested or inferred to be positive for BRCA1/2 mutations and 392 family members tested as mutation negative) has been transferred to CGB. The first priority with regard to these families is to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members. Concurrently, we will mount a carefully-designed research protocol for these same individuals. This project will address issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing, endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. The Concept and Protocol related to this study are now under development. The first component of this study to begin patient accrual is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer. This protocol has cleared both the DCEG scientific review process and and has been approved by the Clinical Center IRB and is expected to enroll its first subjects within the next several months. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics, and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis tool in this setting, and as a potential source of biological materials for molecular genetic studies. A study of the prevalence of BRCA1/2 founder mutations is now underway in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995. The genetic testing on these samples is expected to be completed before the end of the year. In collaboration with the Laboratory of Pathology/DCS, a systematic comparison of the histopathology of BRCA1/2 mutation associated prostate cancers with that of cancers not associated with such mutations is planned. We also will perform loss of heterozygosity studies on BRCA1,2-associated prostate cancers. The goal of this study is to resolve the current uncertainty regarding whether prostate cancer is one of the features of the BRCA1,2 syndromes. If the answer proves to be "yes," this will provide the rationale for proceeding with a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Ovarian Cancer Early Detection Resource Network (EDRN), plans are well underway to mount a national, prospective follow-up study of genetically at-risk women who elect to undergo prophylactic oophorectomy. This will permit us to address such issues as: (a) what is the prevalence of clinically occult ovarian cancer at the time of prophylactic oophorectomy? (b) are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) what is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to this operation? and (d) how does this surgical procedure affect the quality of life for the women who elect it? Another major issue related to BRCA1,2-associated ovarian cancer is the lack of effective screening measures for this often lethal disease. A Workshop has been scheduled for April 2001 to address this deficiency and to attempt to identify novel screening strategies which warrant further clinical evaluation. We are also negotiating a collaboration with an extra-mural investigator who has collected a large, population-based series of ovarian cancer cases and controls. The intent would be to determine the BRCA1/2 mutation status of the subjects in this study, providing both a more accurate estimate of the proportion of ovarian cancers which can be attributed to this genetic alteration, and permitting a detailed analysis of how mutation status and exposure to oral contraceptives interact with regard to ovarian cancer risk. It is vital to determine whether women at hereditary risk of ovarian cancer experience the same protective benefit from the use of oral contraceptives as that which has been documented among women in the general population. We have initiated development of a multidisciplinary research program which will focus on the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors as well. Fanconi's Anemia is the prototype of these diseases, which also include dyskeratosis congenita, Diamond-Blackfan syndrome and Schwachman-Diamond syndrome. These rare disorders will be used as models for studying mechanisms of carcinogenesis in humans. This opportunity has been created by the recruitment of a prominent clinical investigator (Dr. Blanche P. Alter), who has an international reputation in both the clinical management and the laboratory assessment of patients with these disorders. As the staff of CGB increases in number, it is expected that additional, less well studied familial/inherited cancer susceptibility disorders will be selected for study. The first of these is familial testicular cancer, an entity in which DCEG has had an intermittent interest in over the years. The recent mapping of a testicular cancer susceptibility gene to the X chromosome, coupled with the impending activation of a new, large testicular cancer case-control study by epidemiology colleagues in the Environmental Epidemiology Branch have resulted in CGB committing to a major familial testicular cancer project. We have joined the International Testicular Cancer Linkage Consortium, and contributed to their gene mapping/cloning efforts DNA from a series of families previously studied at NCI some years ago. We are negotiating to take the lead in a central review of the testicular cancer pathology and an analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. A mechanism for accruing new testicular cancer families has been developed, and we expect to acquire DNA for positional cloning purposes from them, as well as to invite selected families to the NIH Clinical Center for a more detailed, etiologically oriented, clinical/genetic/laboratory study of the type that has historically been done so well by DCEG investigators. The combination of breast cancer and colon cancer in different members of the same family seems to occur more often than can be accounted for by the known hereditary cancer syndromes. We are planning a family/genetic study of women with double primary cancers of the breast and colon in an effort to clarify this association. Evidence for an as yet unidentified cancer susceptibility gene will be sought. High on the list of other likely studies is the systematic investigation of familial hematopoietic and lymphoproliferative disorders, with special attention to families with multiple different cancers of this type. This would build on prior DCEG studies of familial Hodgkins and acute leukemia, and current studies of familial non-Hodgkins lymphoma, chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia. CGB will also play a role, as needed, in the analysis of family history data collected as part of ongoing analytic epidemiology studies conducted by colleagues elsewhere within DCEG. The first such project entails an assessment of family history of cancer and level of Westernization as cancer risk factors in a population-based, case-control study of breast cancer in Asian American women. This is being done through a collaboration with investigators in the Epidemiology and Biostatistics Program, and the Genetic Epidemiology Branch.