Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

临床遗传学分部（CGB）是NCIs开展临床癌症遗传学转化研究活动的基地。CGB从多学科、流行病学的角度来理解基因在癌症的起因、治疗和预防中的作用；为高危个人和家庭制定综合管理战略；培训下一代临床癌症遗传学研究人员。<BR><BR><B>遗传性乳腺癌/卵巢癌</B><BR><BR> DCEG从20世纪60年代开始研究遗传性乳腺癌/卵巢癌（HBOC）综合征；它现在包括一个遗传疾病范例，用于解决重要的转化研究问题。我们使用了32个BRCA突变阳性家族的前瞻性队列，具有广泛的临床和流行病学信息，以及生物样本[NCI协议#02-C-0212]</B>。在过去的一年里，有86个新的突变阳性家庭登记。研究亮点包括在BRCA突变阳性家族的前瞻性队列中，记录了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62%，作为BRCA1/2修饰因子研究联盟（CIMBA）项目的一部分，一系列重要的阳性和明确阴性的候选基因研究分析了< 1/ 1 BRCA1/2< 1/ 1 >相关乳腺癌风险的遗传修饰因子。以及一系列关于HBOC家庭进行遗传风险评估的早期经验的咨询/社会心理报告。最值得注意的与cimba相关的发现包括证实RAD51显著改变brca2相关乳腺癌的风险，FGFR2和TNRC9在brca相关乳腺癌的风险中发挥重要作用。遗传性骨髓衰竭综合征（IBMFS）研究项目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员，对范可尼贫血（FA）和相关疾病有长期的兴趣，这些疾病都有再生障碍性贫血、骨髓增生异常综合征（MDS）、急性髓性白血病（AML）和选定的实体瘤。她的综合多学科方案代表了首次以流行病学为基础，以病因学为重点的对这些罕见疾病的调查[NCI方案#02-C-0054]。迄今为止，来自近200个家庭的754名同意成员已被纳入。迄今为止的主要发现包括细化的FA相关癌症风险定量估计，基于临床表型的模型，预测FA关键结果（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相关头颈部鳞状细胞癌的内在超额风险，对BRCA2中导致fanc1 - d1的双等位基因突变进行了有洞察力的假设生成分析。发现高脂血症和骨质疏松症是FA临床表型的一部分，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，以及极短的端粒可以作为先天性角化不良的诊断试验的重大发现。家族性睾丸生殖细胞肿瘤研究代表了一种研究不充分的家族性癌症疾病，正在两种新方案下进行评估，一种是积累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协议#02-C-0178</B>]，另一种是旨在定位和克隆新的TGCT易感基因。与国际睾丸癌连锁联盟（ITCLC）合作[NCI协议#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人已在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发现，睾丸微石症在TGCT亲属中比预期的更常见，并且倾向于聚集在一个亚组家庭中（提高了遗传易感微石症的可能性），在迄今报道的最大的家族性TGCT （FTGCT）患者中没有体质细胞遗传学异常。认识到一种可能的新的FTGCT综合征，其特征是肾脏和垂体肿瘤、结肠息肉、脂肪瘤和慢痣，并且在这种疾病中没有畸形表型，这被认为起源于子宫内发育。我们为ITCLC的基因发现活动贡献了58个新的FTGCT的389个DNA样本，使我们成为该合作的第二大贡献者。这项工作的观察结果包括：对295个多病例家族的全基因组连锁筛选，没有证实先前在染色体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；鉴定Y染色体gr/gr缺失是TGCT风险的第一个遗传修饰因子（家族性和散发性）（55）；排除小鼠DND1 TGCT易感基因作为人类TGCT的候选基因；并对ITCLC登记处的469个TGCT家族（包含1002例TGCT病例）进行了描述性分析，结果显示家族性和散发性TGCT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亚群。<BR><BR><B>其他家族性癌症综合征</B><BR><BR>泌尿道家族性移行细胞癌（FTCCUT）是另一种研究不足的家族性癌症综合征，也是DCEG研究人员的历史兴趣之一。我们一直在探索对这种综合征开展多学科、病因学研究的可能性。我们提交了一篇有关泌尿道恶性肿瘤遗传决定因素的文献综述。目前，由于担心没有足够数量的高风险家庭可供研究，该项目的进一步发展被搁置。<BR><BR>< BR b>家族性癌症的遗传咨询、社会心理和行为研究</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。在过去4年中，出版了21份手稿，目前正在审查另外5份手稿。目前正在完成的手稿包括对BRCA1/2突变阳性家庭妇女补充和替代药物使用的分析；FTC高危亲属的睾丸自检实践；HBOC家庭的家庭沟通模式（社会网络分析）。正在进行的分析包括验证我们在卵巢癌风险增加的妇女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；与乳腺癌/卵巢癌筛查结果相关的模糊性作为情绪和筛查行为的调节剂范可尼贫血家族成员骨髓移植决策的影响因素对癌症风险增加的男性进行CEGRM评估；以及FTC家庭成员的一般癌症筛查行为模式（Jennifer Loud）。我们已经证明了将这种类型的研究作为我们临床研究方案的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，其速度取决于我们是否有能力聘请具有适当专业知识的终身研究员。最后，我们正在开发一种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

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