Genome-Wide molecular epidemiology of treatment outcome and cancer risk

治疗结果和癌症风险的全基因组分子流行病学

• 批准号: 8544796
• 负责人: FEDERICO INNOCENTI
• 金额: $ 13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544796
• 关键词: Address; Angiogenesis Inhibitors; Bioinformatics; Biological; Biological Process; Cancer Patient; Candidate Disease Gene; Carcinogens; Chemotherapy-Oncologic Procedure; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Computer Simulation; DNA Resequencing; Data; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Human; Human Genetics; In Vitro; Individual; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Study; Malignant Neoplasms; Mentors; Molecular; Molecular Epidemiology; Molecular Genetics; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase III Clinical Trials; Population; Predisposition; Prevalence; Randomized; Research; Research Training; Resources; Role; Series; Single Nucleotide Polymorphism; Surveys; Techniques; Technology; Testing; Toxic effect; Training; Treatment outcome; Variant; Work; angiogenesis; antiangiogenesis therapy; base; cancer risk; cancer therapy; chemotherapy; design; epidemiology study; experience; genetic epidemiology; genome wide association study; genome-wide; novel; programs; risk benefit ratio; therapy design; therapy outcome

DESCRIPTION (provided by applicant): The goal of this mentored career development award application is to consolidate my diverse training experiences in laboratory and clinical pharmacology, human genetics, and clinical investigation into a focused research program in "Genome-wide molecular epidemiology of treatment outcome and cancer risk". The purpose of this program will be to discover and test the biological function of novel germline genetic variation that might serve as markers of 1) severe toxicity and survival in cancer patients treated with chemotherapy, and 2) cancer susceptibility. These markers will be identified through genome-wide (GW) association studies (GWAS), and my previous training and research experience do not pertain to GW investigations. To undertake research that combines GW data with molecular, genetic, epidemiology and bioinformatics techniques, I will be required to apply these technologies to genomic population data. This program will be constructed through a series of clinical, epidemiology, and laboratory studies. I propose to use unbiased genomic approaches for the discovery of novel candidate genes as markers of outcome of chemotherapy. The same approaches will be also applied to identify novel candidates of cancer susceptibility by benefiting from publicly available resources of GW information from control individuals without cancer. Enrichment of the information generated from the GW data will be derived from additional genotyping and/or resequencing of genomic regions that showed significant associations in the GWAS. It is very likely that the significant single nucleotide polymorphisms (SNPs) in the GWAS will not have an established molecular function, and several strategies will be used to support the observed clinical associations. The proposed research plan and subsequent investigations will substantially increase the understanding of the pleiotropic effects of heritable genetic information in humans. This work will provide a knowledge framework for designing controlled replication studies of treatment outcome and cancer risk using highly selected informative markers. These applications could inform interventions designed to establish the risk-benefit ratio of cancer chemotherapy and to reduce the prevalence of cancer in the population.

描述（由申请人提供）：这一指导职业发展奖的目的是巩固我在实验室和临床药理学，人类遗传学和临床研究中对“治疗结果和癌症风险的全基因组分子流行病学”的重点研究计划的临床研究的多种培训经验。该程序的目的是发现和测试新型种系遗传变异的生物学功能，该差异可能是1）用化学疗法治疗的癌症患者的严重毒性和生存的标志，以及2）癌症敏感性。这些标记将通过全基因组（GW）协会研究（GWAS）来识别，我以前的培训和研究经验与GW的研究无关。为了进行将GW数据与分子，遗传，流行病学和生物信息学技术相结合的研究，我将需要将这些技术应用于基因组人群数据。该计划将通过一系列临床，流行病学和实验室研究来构建。我建议使用公正的基因组方法来发现新型候选基因作为化学疗法结果的标志。还将采用相同的方法来通过从没有癌症的对照人的GW信息中受益，以识别癌症易感性的新型候选者。从GW数据中产生的信息的丰富将来自基因组区域的其他基因分型和/或重新取代，这些区域在GWAS中显示出显着关联。 GWAS中重要的单核苷酸多态性（SNP）很可能不会具有建立的分子功能，并且将使用几种策略来支持观察到的临床关联。 拟议的研究计划和随后的研究将大大增加对人类遗传信息的多效性影响的理解。这项工作将提供一个知识框架，用于使用高度选择的信息标记来设计对治疗结果和癌症风险的受控复制研究。这些应用可以为旨在建立癌症化学疗法的风险效益比的干预措施提供信息，并降低人群中癌症的患病率。

项目成果

The influence of UGT polymorphisms as biomarkers in solid organ transplantation.

• DOI: 10.1016/j.cca.2012.01.031
• 发表时间: 2012-09-08
• 期刊: Clinica chimica acta; international journal of clinical chemistry
• 作者: Dupuis R;Yuen A;Innocenti F
• 通讯作者: Innocenti F

Systemic therapies for pancreatic cancer--the role of pharmacogenetics.

• DOI: 10.2174/138945012800564068
• 发表时间: 2012-06
• 期刊: Current drug targets
• 影响因子: 3.2
• 作者: Soo RA;Yong WP;Innocenti F
• 通讯作者: Innocenti F

Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era.

• DOI: 10.1038/clpt.2013.214
• 发表时间: 2014-03
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7

A guide to the current Web-based resources in pharmacogenomics.

• DOI: 10.1007/978-1-62703-435-7_19
• 发表时间: 2013-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Glubb, Dylan M;Paugh, Steven W;Innocenti, Federico
• 通讯作者: Innocenti, Federico

A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen.

• DOI: 10.1038/tpj.2012.31
• 发表时间: 2013-10
• 期刊: The pharmacogenomics journal
• 作者: Cecchin E;D'Andrea M;Lonardi S;Zanusso C;Pella N;Errante D;De Mattia E;Polesel J;Innocenti F;Toffoli G
• 通讯作者: Toffoli G