Clinical/Genetic Studies of Family/Hereditary Cancers

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。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。所有家庭都已被告知他们的突变状况，目前正在将感兴趣的家庭成员带到临床中心进行遗传风险评估、咨询、基因检测和结果披露。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。该协议正在积极进行中。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。遗传性乳腺癌/卵巢癌项目也提供了在CGB内开展行为/社会心理研究项目的机会。这项活动将针对癌症遗传风险增加的个人，并将利用最近招聘的工作人员的专业知识，包括遗传咨询师、精神病学社会工作者和癌症遗传学研究护士。这个项目是在NCI癌症控制和人口研究部门的高级行为研究者的支持下开发的。初步评估将侧重于参与乳腺成像研究的受试者的经验。我们期望将这一努力扩展到参与遗传性骨髓衰竭综合征研究的人群中探索一系列重要问题。1994 - 1995年间，一项关于1000名德系以色列前列腺癌患者BRCA1/2始祖突变患病率的研究即将完成。初步分析表明，在突变携带者中，前列腺癌的发病率增加了两倍。突变相关和突变不相关的组织病理学没有重大差异。我们正在完成在前列腺癌肿瘤组织中寻找BRCA1/2基因位点杂合性缺失的实验室研究。这些发现为继续进行HBOC突变携带者家族男性前列腺癌筛查和预防研究提供了更坚实的理论依据。这个新项目的规划正处于起步阶段。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）和癌症遗传学网络的研究人员合作，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？选择保留卵巢的妇女将接受一种基于CA125水平随时间变化率的新型卵巢癌筛查算法的监测。这项研究应于2001年历年年底开始累积。我们的多学科研究项目针对易导致骨髓衰竭、急性白血病和成人幸存者实体瘤的遗传性儿科疾病，刚刚提交了IRB批准。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。特别是，我们将分析HPV在口腔和女性生殖器恶性肿瘤的病因学中可能起的作用，这些肿瘤在这种情况下经常发生。将进行基因型/表型相关性分析。将努力确定FA基因有害突变的杂合（携带者）是否有更高的癌症风险。我们预计在2002年年初开始病人计提。重新激活DCEG对家族性睾丸癌兴趣的计划正在顺利进行。我们正积极与国际睾丸癌连锁联盟合作，开展一系列与这种罕见的家族性癌症综合征相关的研究。CGB研究人员率先设计了一项关于睾丸癌病理的中心综述，并对Consortium家族中生殖细胞肿瘤以外的癌症的发生进行了定量分析。与这两个项目有关的数据收集工作应于2002年初开始。此外，我们正在最终确定一个与积累新的睾丸癌家族相关的概念。这些家族将为x连锁睾丸癌易感基因TGCT1的定位克隆提供DNA，并允许对假定的其他常染色体易感基因进行基因组扫描。感兴趣的家庭将被带到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研究人员做得很好。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。我们正在完成与此关联相关的文献综述，这将作为计划双原发乳腺癌和结肠癌妇女的家庭/遗传研究的基础，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。CGB正在与遗传流行病学处合作，努力开发一种综合方法来评估淋巴增生性恶性肿瘤家庭。这将建立在目前对家族性CLL、Waldenstrom巨球蛋白血症和非霍奇金淋巴瘤的研究基础上。我们有机会研究家族性多发性骨髓瘤和家族性急性白血病。我们的目标是设计一种研究策略，使我们能够解释这样一个事实，即这些癌症的聚类倾向于在家庭中是异质的，而不是肿瘤类型特异性的。我们打算研究到目前为止尚未得到充分评估的其他家族性癌症综合征。目前正在考虑家族性胃癌和家族性膀胱癌的研究。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。初步结果表明，环境风险因素和遗传风险因素在移居美国的亚洲血统妇女乳腺癌病因学中可能存在协同作用。CGB还将大量的注意力和工作人员的精力用于培训对临床癌症遗传学感兴趣的各种卫生保健专业人员和研究人员。我们的第一位博士预科生即将完成她的流行病学博士论文。她正在分析乳腺癌家族史与参与DCEG对BCDDP队列随访的女性患子宫内膜癌或卵巢癌风险之间的关系。我们现在有两个博士后癌症遗传学研究员和我们一起工作，一个是医学遗传学博士，另一个是医学博士，医学肿瘤学委员会认证。我们最近被美国遗传咨询师委员会认证为参与NHGRI/约翰霍普金斯大学公共卫生学院联合硕士项目的遗传咨询师研究生的官方临床培训地点。

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). The first priority with regard to these families is to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members. All families have been notified of their mutation status, and the process of bringing interested family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure is now underway. 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 is actively underway. 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. The hereditary breast/ovarian cancer project has also provided the opportunity to initiate development of a behavioral/psychosocial research program within CGB. This activity will target individuals at increased genetic risk of cancer, and will draw upon the expertise of recently-recruited staff, including a genetic counselor, a psychiatric social worker and a cancer genetics research nurse. This project is being developed with the support of senior behavioral investigators from NCI's Division of Cancer Control and Population Studies. Initial assessment will focus on the experience of subjects participating in the Breast Imaging Study. We anticipate extending this effort to explore a series of important issues among persons participating in the Inherited Bone Marrow Failure Syndromes Study. A study of the prevalence of BRCA1/2 founder mutations is nearing completion in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995. Preliminary analyses suggest a two-fold excess of prostate cancer among mutation carriers. No major differences in histopathology between mutation-related and mutation-unrelated have been identified. We are finishing laboratory studies to seek loss of heterozygosity at the BRCA1/2 gene loci in prostate cancer tumor tissue. These findings provide a more solid rationale for proceeding with a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. Planning for this new project is in its beginning stages. 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 Cancer Genetics Network, 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? Women who elect to retain their ovaries will be monitored with a novel ovarian cancer screening algorithm based on rate-of-change of CA125 levels over time. This study should begin accrual by the end of calendar year 2001. Our multidisciplinary research program targeting the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors has just been submitted for IRB approval. 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. In particular, we will analyze the possible role of HPV in the etiology of the oral cavity and female genital malignancies which occur excessively in this setting. Genotype/phenotype correlations will be performed. An effort will be made to determine if persons who are heterozygous (carriers) for deleterious mutations in the FA genes are at increased risk of cancer. We anticipate initiating patient accrual in early 2002. Plans to re-activate DCEG's interest in familial testicular cancer are well underway. We are actively collaborating with the International Testicular Cancer Linkage Consortium in a series of studies related to this rare familial cancer syndrome. CGB investigators have taken the lead in designing a central review of the testicular cancer pathology and a quantitative analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. Data collection related to these two projects should begin in early 2002. In addition, we are finalizing a concept related to accruing new testicular cancer families. These families will contribute DNA for positional cloning of the X-linked testicular cancer susceptibility gene TGCT1, and to permit genome scanning for presumed additional autosomal susceptibility genes as well. Interested families will be broght 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 completing a literature review related to this association, which will serve as a basis for 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. CGB is collaborating with the Genetic Epidemiology Branch in an effort to develop a comprehensive approach to the evaluation of families with lymphoproliferative malignancies. This will build on current studies of familial CLL, Waldenstrom's macroglobulinemia and non-Hodgkin's lymphoma. Opportunities have developed which may permit us to study familial multiple myeloma and familial acute leukemia. The goal is to design a research strategy that will allow us to explain the fact that the clustering of these cancers tends to be heterogeneous within families, rather than tumor type specific. We intend to study additional familial cancer syndromes which, thus far, have been inadequately evaluated. Under consideration at the present time are studies of familial gastric cancer and familial bladder cancer. 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. Preliminary results suggest a possible synergism between environmental risk factors and genetic risk factors in the etiology of breast cancer among women of Asian ancestry who migrate to the United States. CGB is also devoting significant attention and staff energy to the training of various health care professionals and researchers with an interest in clinical cancer genetics. Our first pre-doctoral candidate is nearing completing of her PhD thesis in epidemiology. She is analyzing the relationship between family history of breast cancer and the risk of developing either endometrial or ovarian cancer among women participating in DCEG's follow-up of the BCDDP cohort. We now have two post-doctoral cancer genetics fellows working with us, one a PhD in medical genetics and the other an MD, board-certified in medical oncology. We have recently been certified by the American Board of Genetic Counselors as an official clinical training site for genetic counselor graduate students who are enrolled in the joint NHGRI/Johns Hopkins University School of Public Health masters' program.