Fanconi Defects in Pancreatic Cancer Oncogenesis

胰腺癌肿瘤发生中的范科尼缺陷

• 批准号: 7904013
• 负责人: SCOTT E KERN
• 金额: $ 30.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904013
• 关键词: Address; African American; Alleles; American; Antibodies; Attention; BRCA2 Mutation; BRCA2 gene; Biochemical; Biological Assay; Cancer Etiology; Cancer Family; Cancer Patient; Cell Line; Cell model; Cells; Cessation of life; Chemoprevention; Classification; Clinical; Clinical Trials; Clinical Trials Design; DNA; DNA Damage; Databases; Defect; Diagnosis; Diagnostic; Distal; Engineering; Enrollment; Exons; Experimental Models; FANCG gene; Family; Fanconi' s Anemia; First Degree Relative; Follow-Up Studies; Frequencies; Funding; Gene Mutation; Gene with Unknown or Unclassified Function; General Population; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Germ-Line Mutation; Goals; Grant; Health; Human; Hypersensitivity; Immunofluorescence Immunologic; In Vitro; Inherited; Knock-in Mouse; Knock-out; Knowledge; Laboratories; Libraries; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Methods; Minority; Missense Mutation; Modeling; Mono-S; Mutagenesis; Mutate; Mutation; Null Lymphocytes; Organism; Ovarian; Pancreas; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Phase; Phenotype; Play; Polymerase; Population; Predisposition; Prevalence; Progress Review Group; Proteins; Radiation; Reagent; Recommendation; Registries; Reporting; Research; Resources; Risk; Risk Estimate; Role; Severities; Signal Transduction; Site; Somatic Cell; Specific qualifier value; Subgroup; Surveys; Techniques; Technology; Testing; Therapeutic; Topoisomerase II; Translational Research; Treatment Protocols; Tumor Biology; Ubiquitin; Ubiquitination; United States; Variant; Vertebral column; arm; base; cancer cell; cancer risk; cancer type; cellular engineering; clinically relevant; crosslink; design; experience; genetic variant; homologous recombination; human TOP1 protein; improved; inhibitor/antagonist; interest; knockout gene; malignant breast neoplasm; member; novel; public health relevance; pyrroloquinoline; resistance mechanism; response; theories; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Tumor-associated mutations in the FA (Fanconi anemia) genes offer exciting opportunities for chemoprevention, diagnosis, and tailored therapy for pancreatic, ovarian, and breast cancer. No cancer type has a higher proportion of FA-mutated tumors than pancreatic cancer. A decade ago, we initiated the first registry of pancreatic cancer families having FA mutations. We found mutations in BRCA2, FANCC, and FANCG in pancreatic cancers, a classic example of a high-frequency low-penetrance population risk with high clinical importance. The FA gene mutations convey a hypersensitivity to certain drugs and radiation, but clinically important questions arose when we observed the level of sensitivity to differ, depending on which FA gene was mutated. We recently initiated a trial to treat FA-deficient cancers using a drug to which they are specifically hypersensitivity. To our knowledge this is the first U.S. clinical cancer trial in which the indicated drug is specified by an analysis of germline DNA mutations. Yet, the laboratory components of the trial and its design have never attained funding by a specific grant. Considerable improvements in trial design are likely if translational research aims can be pursued at an appropriate pace. Interest in the correct classification of deleterious mutations is raised by our experience with familial registry and the new trial. We encounter many inherited missense germline FA gene mutations of unclassified significance. They are very common within the general population, but for most it is not known whether they are normal polymorphisms or cancer-causing. We recently explored key technical breakthroughs to better to permit diagnosis and testing of FA defects, and cellular models accelerating this research. Our specific aims employ a new experimental model of somatic cell FA genes knockouts and knock-in of missense variants in cancer cells, generating and evaluating mutation-specific and gene-specific phenotypes and aiding patient management through improved diagnostic and allele-interpretive techniques. Our long-term goal is to understand the roles of FA defects in tumor progression, to understand with precision the distinctions among clinically relevant phenotypic changes produced by different gene mutations, and to identify clinically important patient subgroups. PUBLIC HEALTH RELEVANCE: The most common known causes of familial pancreatic cancer are mutations in a Fanconi gene (specifically, BRCA2). We found mutations of BRCA2 and other Fanconi genes in pancreatic cancers; the mutations are of high clinical importance, for they determine the risk of developing cancer and now also sometimes determine the treatment protocol to which a patient can enroll. Recent advances will allow us now to efficiently explore improved diagnosis and therapeutic assignment of these patients.

描述（由申请人提供）：FA（范可尼贫血）基因中的肿瘤相关突变为胰腺癌、卵巢癌和乳腺癌的化学预防、诊断和定制治疗提供了令人兴奋的机会。没有一种癌症类型的 FA 突变肿瘤比例高于胰腺癌。十年前，我们启动了第一个具有 FA 突变的胰腺癌家族登记。我们在胰腺癌中发现了 BRCA2、FANCC 和 FANCG 突变，这是具有高度临床重要性的高频低外显率人群风险的典型例子。 FA 基因突变会导致对某些药物和辐射过敏，但当我们观察到敏感性水平因突变的 FA 基因而异时，出现了临床上重要的问题。我们最近启动了一项试验，使用一种对 FA 缺乏的癌症特别敏感的药物来治疗它们。据我们所知，这是美国第一个临床癌症试验，其中通过种系 DNA 突变分析来指定指定药物。然而，该试验的实验室组成部分及其设计从未获得特定拨款的资助。如果能够以适当的速度实现转化研究目标，试验设计可能会得到相当大的改进。我们在家族登记和新试验方面的经验引起了人们对有害突变的正确分类的兴趣。我们遇到许多具有未分类意义的遗传性错义种系 FA 基因突变。它们在普通人群中非常常见，但对于大多数人来说，尚不清楚它们是正常的多态性还是致癌性。我们最近探索了关键技术突破，以更好地诊断和测试 FA 缺陷，并通过细胞模型加速这项研究。我们的具体目标是采用一种新的体细胞 FA 基因敲除和错义变异敲入实验模型，生成和评估突变特异性和基因特异性表型，并通过改进的诊断和等位基因解释技术帮助患者管理。我们的长期目标是了解 FA 缺陷在肿瘤进展中的作用，准确了解不同基因突变产生的临床相关表型变化之间的区别，并确定临床上重要的患者亚组。公共健康相关性：家族性胰腺癌最常见的已知原因是 Fanconi 基因（特别是 BRCA2）突变。我们在胰腺癌中发现了 BRCA2 和其他 Fanconi 基因的突变；这些突变具有很高的临床重要性，因为它们决定了患癌症的风险，现在有时还决定了患者可以参加的治疗方案。最近的进展将使我们能够有效地探索改进这些患者的诊断和治疗分配。