Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

家族性和遗传性癌症综合征的临床遗传学研究

• 批准号: 7593182
• 负责人: MARK H GREENE
• 金额: $ 41.12万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593182
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Aplastic Anemia; BRCA2 gene; Behavior; Behavioral; Biological; Biological Markers; Bone Marrow Transplantation; Breast; Cancer Family; Cancer-Predisposing Gene; Candidate Disease Gene; Caring; Cessation of life; Characteristics; Chromosome abnormality; Chromosomes; Class; Clinical; Clinical Research Protocols; Cloning; Collaborations; Colonic Polyps; Communication; Consent; Constitutional; Counseling; DNA; Decision Making; Development; Diagnostic tests; Disease; Division of Cancer Epidemiology and Genetics; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Enrollment; Exclusion; Eye; FGFR2 gene; Failure; Family; Family Study; Family member; Fanconi' s Anemia; Future; Genes; Genetic; Genetic Counseling; Genetic Determinism; Genetic Predisposition to Disease; Hand; Head and neck structure; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Disease; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Human; Hyperlipidemia; Individual; Inherited; International; International Aspects; Investigation; Kidney; Laboratories; Learning; Lipoma; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of ovary; Malignant neoplasm of testis; Manuscripts; Maps; Marrow; Modeling; Moods; Mus; Mutation; Neutropenia; Numbers; Operative Surgical Procedures; Osteoporosis; Outcome; Pancytopenia; Participant; Pathogenesis; Pathway Analysis; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Phenotype; Pituitary Neoplasms; Play; Population; Protocols documentation; Publishing; Quality of life; Rare Diseases; Recruitment Activity; Registries; Reporting; Research; Research Activity; Research Design; Research Personnel; Resources; Review Literature; Risk; Role; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Screening for cancer; Screening procedure; Series; Social Network; Solid Neoplasm; Stress; Susceptibility Gene; Syndrome; Testicular Germ Cell Tumor; Testing; Thinking; Tissue Banks; Training; Transitional Cell Carcinoma; Translational Research; Transplantation; United States National Institutes of Health; Urinary tract; Validation; Woman; Y Chromosome; anticancer research; base; cancer genetics; cancer prevention; cancer risk; career; clinical phenotype; cohort; early experience; gene discovery; genetic analysis; genetic epidemiology; genetic risk assessment; genome-wide linkage; interest; kindred; malignant breast neoplasm; member; men; mindfulness-based stress reduction; multidisciplinary; mutation carrier; next generation; novel; predictive modeling; programs; prospective; psychosocial; telomere; testicular self examination

The Clinical Genetics Branch (CGB) is NCIs base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators.<BR><BR><B>Hereditary Breast/Ovarian Cancer </B><BR><BR> DCEG has been studying the Hereditary Breast/Ovarian Cancer (HBOC) syndrome since the 1960s; it now comprises a genetic disease paradigm for addressing vital translational research questions. We use a prospective cohort of 32 BRCA mutation-positive families with extensive clinical and epidemiologic information, and biological samples [<B>NCI Protocol #02-C-0212]</B>. 86 new mutation-positive families have enrolled during the past year. Research highlights include documenting a 62% reduction in breast cancer risk among women undergoing risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA mutation-positive families, a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of <i>BRCA1/2</i>-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. The most noteworthy CIMBA-related findings include confirmation that RAD51 significantly modifies the risk of BRCA2-related breast cancer, and that FGFR2 and TNRC9 play important roles in the risk of BRCA-related breast cancer. <BR><BR><B>Inherited Bone Marrow Failure Syndromes (IBMFS) Study</B><BR><BR> The Inherited Bone Marrow Failure Syndromes (IBMFS) Program is our second major hereditary cancer project, led by Dr. Blanche Alter, a world-class clinical and laboratory investigator with a career-long interest in Fanconi anemia (FA) and related disorders, which all share a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and selected solid tumors. Her comprehensive, multidisciplinary protocol represents the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders [<B>NCI Protocol #02-C-0054</B>]. To date, 754 consented members from nearly 200 families have been enrolled. Major findings to date include refined, quantitative estimates of FA-related cancer risks, a model based on clinical phenotype which predicts the risk of critical FA outcomes (marrow failure, transplant, cancer and death), the first description of how bone marrow transplant amplifies the intrinsic excess risk of FA-related squamous cell cancers of the head/neck, an insightful, hypothesis-generating analysis of the bi-allelic mutations in BRCA2 which cause FANC-D1, the discovery that hyperlipidemia and osteoporosis are part of the FA clinical phenotype, a novel hypothesis regarding the pathogenesis of acute leukemia in patients with severe congenital neutropenia, and the high-impact discovery that very short telomeres represent a diagnostic test for dyskeratosis congenita.<BR> <BR><B>Familial Testicular Cancer</B><BR><BR>The Familial Testicular Germ Cell Tumor study represents an inadequately-studied familial cancer disorder being evaluated under two new protocols, one accruing and evaluating a series of new multiple-case families (the NCI Testicular Germ Cell Tumor TGCT Study) [<B>NCI Protocol #02-C-0178</B>], and a second, aimed at mapping and cloning new TGCT susceptibility genes, in collaboration with the International Testicular Cancer Linkage Consortium (ITCLC) [NCI Protocol #04-C-N076]. Through the former, we have enrolled 506 consented members (136 of whom have been evaluated at the NIH Clinical Center) from 100 newly-ascertained families. Findings from this multidisciplinary, etiologically-oriented family study include recognition that testicular microlithiasis is more common than expected in TGCT kindred, and tends to cluster in a sub-set of families (raising the possibility of a genetic predisposition to microlithiasis), the absence of constitutional cytogenetic abnormalities in the largest series of familial TGCT (FTGCT) patients yet reported, recognition of a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lipomas and lentigenes, and the absence of a dysmorphic phenotype in this disorder, which is thought to originate during intra-uterine development. We have contributed 389 DNA samples from 58 new FTGCT kindred to the gene discovery activities of the ITCLC, making us the second largest contributor to that collaboration. Observations reported from this effort include a genome-wide linkage screen of 295 multiple-case families which did not confirm the prior finding of a candidate locus on chromosome Xq27, but rather suggested that multiple low-penetrance genes acting in concert may underlie FTGCT, identification of the Y chromosome gr/gr deletion as the first genetic modifier of TGCT risk (both familial and sporadic) (55), exclusion of the mouse DND1 TGCT susceptibility gene as a candidate for human TGCT, and a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases) in the ITCLC registry, which demonstrated surprising similarity between the characteristics of familial and sporadic TGCT, and an absence of readily-recognizable phenotypic family subsets. <BR><BR><B>Other Familial Cancer Syndromes</B><BR><BR> Familial Transitional Cell Carcinoma of the Urinary Tract (FTCCUT) represents another inadequately-studied familial cancer syndrome, one in which DCEG investigators have an historical interest. We have been exploring the possibility of launching a multidisciplinary, etiologically-focused study of this syndrome. We have submitted a literature review related to genetic determinants of urinary tract malignancy. For the moment, further development of this project is on hold, due to concerns that there simply may not be a sufficient number of high-risk families available for study. <BR><BR><B>Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer </B><BR><BR> is a vital component of CGBs research portfolio, although it has not been designated as an official Program. During the past 4 years, 21 manuscripts have been published, and an additional 5 are currently under review. Manuscripts now being completed include analyses of complementary and alternative medication use in women from BRCA1/2 mutation-positive families; testicular self-examination practices in at risk members of FTC kindred; and family communication patterns in HBOC families (a social network analysis). Ongoing analyses are comprised of validation of our predictive model of choosing between surgery and screening among women at increased risk of ovarian cancer; baseline quality of life among GOG-199 study participants; ambiguity related to breast/ovarian cancer screening test outcome as a modulator of mood and screening behavior; determinants of bone marrow transplant decision-making among Fanconi anemia family members; CEGRM assessment among men at increased cancer risk; and patterns of general cancer screening behavior among FTC family members (Jennifer Loud). We have demonstrated the feasibility and value of performing this type of study as an integral part of our clinical research protocols. Future research will build upon findings from current studies, at a pace influenced by our ability to recruit a tenure-track investigator with appropriate expertise. Finally, we are developing a mindfulness-based, stress reduction program aimed at reducing stress and modifying related biomarkers among BRCA1/2 mutation-carriers

临床遗传学分支 (CGB) 是 NCI 开展校内临床癌症​​遗传学转化研究活动的基地。 CGB 带来了多学科、流行病学的视角： 了解基因在癌症病因、治疗和预防中的作用；为高风险个人和家庭制定综合管理策略； <BR><BR><B>遗传性乳腺癌/卵巢癌</B><BR><BR> DCEG 自 20 世纪 60 年代以来一直在研究遗传性乳腺癌/卵巢癌 (HBOC) 综合征；它现在包含一个解决重要转化研究问题的遗传疾病范例。我们使用了 32 个 BRCA 突变阳性家族的前瞻性队列，这些家族拥有广泛的临床和流行病学信息以及生物样本 [<B>NCI Protocol #02-C-0212]</B>。去年有 86 个新的突变阳性家庭加入。研究亮点包括记录了在 BRCA 突变阳性家庭的前瞻性队列中接受降低风险的输卵管卵巢切除术的女性乳腺癌风险降低了 62%，作为 BRCA1/2 修饰物研究者联盟的一部分，一系列重要的阳性和明确阴性候选基因研究分析了与 <i>BRCA1/2</i> 相关的乳腺癌风险的遗传修饰物 (CIMBA) 项目，以及一系列关于我们与 HBOC 家庭进行遗传风险评估的早期经验的咨询/心理社会报告。最值得注意的 CIMBA 相关发现包括确认 RAD51 显着降低 BRCA2 相关乳腺癌的风险，以及 FGFR2 和 TNRC9 在 BRCA 相关乳腺癌风险中发挥重要作用。 <BR><BR><B>遗传性骨髓衰竭综合征 (IBMFS) 研究</B><BR><BR>遗传性骨髓衰竭综合征 (IBMFS) 计划是我们的第二个主要遗传性癌症项目，由 Blanche Alter 博士领导，她是一位世界级的临床和实验室研究人员，长期对范可尼贫血 (FA) 和相关疾病感兴趣，这些疾病都有一个共同的偏好 用于再生障碍性贫血、骨髓增生异常综合征 (MDS)、急性髓性白血病 (AML) 和特定实体瘤。她的全面、多学科方案代表了对这些罕见疾病的首次基于流行病学、以病因学为重点的调查[<B>NCI 方案#02-C-0054</B>]。迄今为止，已有近 200 个家庭的 754 名同意成员加入。迄今为止的主要发现包括对 FA 相关癌症风险的精确定量估计、基于临床表型的模型，预测关键 FA 结果（骨髓衰竭、移植、癌症和死亡）的风险，首次描述骨髓移植如何放大 FA 相关头/颈鳞状细胞癌的内在超额风险，对 FA 相关的头颈鳞状细胞癌进行富有洞察力的假设生成分析 导致 FANC-D1 的 BRCA2 双等位基因突变、高脂血症和骨质疏松症是 FA 临床表型一部分的发现、关于严重先天性中性粒细胞减少症患者急性白血病发病机制的新假设，以及非常短的端粒代表先天性角化不良的诊断测试的高影响力发现。<BR> <BR><B>家族性睾丸癌</B><BR><BR>家族性睾丸生殖细胞肿瘤研究代表了一种尚未充分研究的家族性癌症疾病，该疾病正在两个新方案下进行评估，一个是累积和评估一系列新的多病例家族（NCI 睾丸生殖细胞肿瘤 TGCT 研究）[<B>NCI 方案 #02-C-0178</B>]，第二个旨在 与国际睾丸癌连锁联盟 (ITCLC) 合作，绘制和克隆新的 TGCT 易感基因 [NCI 方案 #04-C-N076]。通过前者，我们从 100 个新确定的家庭中招募了 506 名同意的成员（其中 136 名已在 NIH 临床中心进行了评估）。这项多学科、以病因学为导向的家庭研究的结果包括认识到睾丸微石症在 TGCT 亲属中比预期更常见，并且倾向于聚集在一个家庭子集中（增加了微石症遗传易感性的可能性），在迄今为止报道的最大系列家族性 TGCT (FTGCT) 患者中不存在体质细胞遗传学异常，认识到 一种可能的新 FTGCT 综合征，其特征是肾和垂体肿瘤、结肠息肉、脂肪瘤和雀斑，并且这种疾病不存在畸形表型，这种疾病被认为起源于子宫内发育过程。我们为 ITCLC 的基因发现活动贡献了来自 58 个新 FTGCT 亲属的 389 个 DNA 样本，使我们成为该合作的第二大贡献者。这项工作报告的观察结果包括对 295 个多病例家族进行全基因组连锁筛查，该筛查并未证实先前在染色体 Xq27 上发现的候选位点，而是表明多个低外显率基因协同作用可能是 FTGCT 的基础，将 Y 染色体 gr/gr 缺失鉴定为 TGCT 风险的第一个遗传修饰因子（家族性和散发性）（55），排除 研究人员将小鼠 DND1 TGCT 易感基因作为人类 TGCT 的候选基因，并对 ITCLC 登记中的 469 个 TGCT 家族（包含 1002 个 TGCT 病例）进行了描述性分析，结果表明家族性和散发性 TGCT 的特征之间存在惊人的相似性，并且缺乏易于识别的表型家族子集。 <BR><BR><B>其他家族性癌症综合征</B><BR><BR> 家族性尿路移行细胞癌 (FTCCUT) 是另一种尚未充分研究的家族性癌症综合征，DCEG 研究人员对这种综合征具有历史兴趣。我们一直在探索对该综合征开展多学科、以病因学为重点的研究的可能性。我们提交了一篇与泌尿道恶性肿瘤遗传决定因素相关的文献综述。目前，由于担心可能没有足够数量的高风险家庭可供研究，该项目的进一步开发被搁置。 <BR><BR><B>家族性癌症的遗传咨询、心理社会和行为研究</B><BR><BR>是 CGB 研究组合的重要组成部分，尽管它尚未被指定为官方项目。过去 4 年里，已发表 21 篇手稿，另有 5 篇正在审稿中。目前正在完成的手稿包括对 BRCA1/2 突变阳性家庭的女性使用补充和替代药物的分析； FTC 亲属高危成员的睾丸自我检查实践； HBOC 家庭中的家庭沟通模式（社交网络分析）。正在进行的分析包括验证我们在卵巢癌风险增加的女性中选择手术和筛查的预测模型； GOG-199 研究参与者的基线生活质量；作为情绪和筛查行为调节剂的乳腺癌/卵巢癌筛查结果的模糊性；范可尼贫血家族成员骨髓移植决策的决定因素；对癌症风险增加的男性进行CEGRM评估； FTC 家庭成员的一般癌症筛查行为模式 (Jennifer Loud)。我们已经证明了进行此类研究作为我们临床研究方案的一个组成部分的可行性和价值。未来的研究将建立在当前研究结果的基础上，其速度取决于我们招募具有适当专业知识的终身教授研究员的能力。最后，我们正在开发一项基于正念的减压计划，旨在减轻 BRCA1/2 突变携带者的压力并修改相关生物标志物