Tooth agenesis as a clinical marker for colon cancer

牙齿发育不全作为结肠癌的临床标志

• 批准号: 8770907
• 负责人: Ariadne M Letra
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770907
• 关键词: Address; Bioinformatics; Biological; Biological Markers; Cancer Family; Candidate Disease Gene; Cessation of life; Clinical; Clinical Data; Clinical Markers; Colon Carcinoma; Complex; Congenital Abnormality; DNA; Data; Databases; Dental; Dentists; Development; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Etiology; Failure; Family; Family history of; Family member; Future; Gene Expression; General Population; Generations; Genes; Genetic; Genetic Counseling; Genetic Variation; Genotype; Goals; Human; In Vitro; Individual; Laboratories; Lead; Light; Link; Malignant Neoplasms; Massive Parallel Sequencing; Mission; Molecular; Motivation; Mutation; National Institute of Dental and Craniofacial Research; Outcome; Pathway interactions; Phenotype; Play; Population; Predisposition; Prevalence; Prevention strategy; Proteins; Records; Recruitment Activity; Relative (related person); Reporting; Research; Risk; Role; Sampling; Signal Transduction; Staging; Testing; Tooth structure; Tumor Suppressor Genes; United States National Institutes of Health; Validation; Variant; Work; base; cancer prevention; colon cancer family registry; congenital anomaly; disease-causing mutation; exome sequencing; familial tooth agenesis; genetic variant; genome-wide; high risk; improved; in vivo Model; molecular marker; next generation sequencing; outcome forecast; permanent tooth; population health; proband; public health relevance; research study; screening; segregation; tool; wisdom tooth

DESCRIPTION (provided by applicant): The goal for this R03 application is to identify causal gene variants linking colon cancer and tooth agenesis. Colon cancer is common and is the second most lethal cancer in the world, with approximately 600,000 related deaths/year worldwide. Tooth agenesis is defined as the failure to develop one or more permanent teeth, and is the most common congenital anomaly in humans. A single report showed the segregation of colon cancer and tooth agenesis in a four-generation Finnish family and suggested a common etiology between the two conditions. However, to date, there have been no systematic clinical or molecular studies of tooth agenesis in colon cancer families to confirm the findings of that initial report and to discover genetic variants contributing to a combined phenotype on a genome-wide scale. For this proposal, we have searched the records of the NIH Colon Cancer Family Registry and selected twenty probands presenting with colon cancer and tooth agenesis, and family history of tooth agenesis, for use in next generation sequencing experiments to identify causal gene variants linking colon cancer and tooth agenesis. Clinical data and DNA samples are readily available in the PI's laboratory. We propose two aims to accomplish this project: (1) DNA samples of the twenty unrelated probands will be subjected to whole exome sequencing (WES) of all known human genes followed by massively parallel sequencing of the captured targets. WES is a powerful approach that has revolutionized our ability to identify disease-causing mutations. Novelty of variants will be assessed by filtering th variants using information that are available in public databases and unlikely disease causing variants will be filtered out. Bioinformatics will be used for candidate gene prioritization, based on predicted functional impact and gene expression data; (2) Prioritized variants will be confirmed in probands and genotyped in selected relatives with tooth agenesis only using Sanger sequencing and/or Sequenom genotyping. The results of this study will allow the identification of gene(s) that are enriched with damaging mutations and thus likely to be contributing to the combined phenotype. Further, the results will delineate a broader phenotype spectrum to which tooth agenesis and colon cancer may belong, and determine if tooth agenesis may be considered an early clinical marker for colon cancer predisposition in susceptible families. The identified variants may be used as screening tools for increased colon cancer susceptibility in additional tooth agenesis families, allowing for improved identification o at-risk families, referral to genetic counseling, and ultimately cancer prevention. The study team presents the expertise and motivation necessary to lead the proposed research. This work will be the basis to a future R01 application to validate or find other variants in additional colon cancer families and tooth agenesis families, and to investigate the molecular mechanisms of the variants identified using in vitro and in vivo models. Finally, the results of this study may revea a paradigm-shifting approach with wide applicability in the dental profession, as dentists will play critical role in identifying families with tooth agenesis at risk for colon cancer.

描述（由申请人提供）：该R 03申请的目标是鉴定连接结肠癌和牙齿发育不全的致病基因变体。结肠癌很常见，是世界上第二大致命癌症，全球每年约有60万人死亡。牙齿发育不全被定义为一个或多个恒牙发育失败，是人类最常见的先天性异常。一份报告显示，在一个四代芬兰家庭中，结肠癌和牙齿发育不全是分离的，并提出了这两种疾病之间的共同病因。然而，到目前为止，还没有系统的临床或分子研究的牙齿发育不全的结肠癌家庭，以确认该初步报告的结果，并发现遗传变异有助于在全基因组范围内的组合表型。对于这个建议，我们已经搜索了NIH结肠癌家族登记处的记录，并选择了20名患有结肠癌和牙齿发育不全的先证者，以及牙齿发育不全的家族史，用于下一代测序实验，以确定连接结肠癌和牙齿发育不全的因果基因变异。临床数据和DNA样本可在PI的实验室随时获得。我们提出了两个目标来完成这个项目：（1）20个无关先证者的DNA样本将进行所有已知人类基因的全外显子组测序（WES），然后对捕获的靶标进行大规模平行测序。WES是一种强大的方法，它彻底改变了我们识别致病突变的能力。将通过使用公共数据库中可用的信息过滤变体来评估变体的新奇性，并将不太可能的致病变体过滤掉。生物信息学将用于候选基因的优先排序，基于 基于预测的功能影响和基因表达数据;（2）仅使用桑格测序和/或Sequenom基因分型，在先证者中确认优先化变体，并在选定的牙齿发育不全亲属中进行基因分型。本研究的结果将允许鉴定富含破坏性突变的基因，因此可能有助于组合表型。此外，研究结果将描绘出牙齿发育不全和结肠癌可能属于的更广泛的表型谱，并确定牙齿发育不全是否可以被认为是易感家族中结肠癌易感性的早期临床标志物。所鉴定的变异体可用作筛选工具，用于在其他牙齿发育不全家族中增加结肠癌易感性，从而改善对高危家族的鉴定，转介遗传咨询，并最终预防癌症。研究小组提出了领导拟议研究所需的专业知识和动机。这项工作将是未来R 01应用的基础，以验证或发现其他结肠癌家族和牙齿发育不全家族的其他变体，并研究使用体外和体内模型鉴定的变体的分子机制。最后，这项研究的结果可能揭示了一个范式转变的方法，在牙科专业具有广泛的适用性，牙医将发挥关键作用，在确定家庭与牙齿发育不全的结肠癌的风险。