Discovering genomic rearrangements under selection in serious ovarian cancer

发现严重卵巢癌选择下的基因组重排

• 批准号: 8354071
• 负责人: Julia Salzman
• 金额: $ 11.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354071
• 关键词: Accounting; Award; Bilateral; Biochemical; Bioinformatics; Candidate Disease Gene; Carcinoma; Cells; Cessation of life; Chromosomal Rearrangement; Clinical; Complex; Cytogenetics; DNA; DNA Sequence Rearrangement; Data; Development; Diagnosis; Double Minutes; Drug Delivery Systems; Early Diagnosis; Early identification; Evolution; Gene Expression Profile; Gene Fusion; Gene Rearrangement; Genes; Genetic; Genetic Variation; Genomics; Goals; Human; Individual; Joints; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mentors; Mentorship; Methods; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Pathogenesis; Pathway interactions; Phase; Prevalence; RNA; Recurrence; Research; Research Personnel; Screening for Ovarian Cancer; Screening procedure; Serous; Solid Neoplasm; Staging; Statistical Methods; Structure; Symptoms; Techniques; Technology; Testing; Tissues; Training; Transcript; Variant; Woman; analytical method; anticancer research; base; cancer genetics; cancer genome; career development; circular RNA; design; genome-wide; improved; innovation; killings; molecular marker; novel; outcome forecast; ovarian neoplasm; pressure; research study; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Recurrent gene fusions and internal tandem duplications are among the most tumor-specific molecular markers known and can provide the potential for therapeutic targets. With a few notable exceptions, however, relatively common recurrent gene fusions have not been identified in commonly occurring carcinomas, which often have multiple, complex chromosomal rearrangements that are difficult to analyze by traditional cytogenetic approaches. Complex tumor karyotpes make it difficult to identify gene fusions using cytogenetics, but suggest the possibility that recurrent rearrangements producing fusions or internal tandem duplications (ITDs) may be prevalent. This proposal aims to use deep sequencing and the novel analytic techniques described to study aspects of the serous ovarian cancer genome and transcriptome which have remained hidden due to limitations in technology or analytical methods, and to test intra- individual and inter-individual selective pressures on tumors. The aspects of this proposal are as follows 1) to further investigate the extent of gene rearrangements in ovarian cancer, focusing on discovering local rearrangements transcribed into RNA; 2) to determine the composition of a group of novel circular transcripts that I have recently found to be expressed at relatively high levels in normal and pathogenic human cells; 3) to characterize double minutes in ovarian cancer, combining bioinformatics to determine rearrangements in their sequence composition and statistical analysis to determine evolutionary pressures on their composition exerted by the tumors. The applicant has a track-record of success in discovering novel gene fusions with ultra-high throughput sequencing (the ESRRA-C11orf20 fusion), as well as designing original rigorous statistical and bioinformatic methods for ultra high throughput data. Under the mentorship of Dr. Patrick O. Brown, a pioneer in high throughput genomic technologies and statistical methods for analyzing them, the applicant will continue career development and training. The first aim of this project will be performed during the mentoring phase, and experiments for aims 2 and 3 will be piloted. The K99/R00 award will support the applicant in her development into an independent investigator who combines statistical and experimental approaches to study cancer genetics. PUBLIC HEALTH RELEVANCE: Ovarian cancer is estimated to kill more than 140,000 women every year and has a poor prognosis once it presents with clinical symptoms. Discovery of truly tumor- specific molecular markers or identification of early and selected amplifications may be essential for effective early detection of serous tumors, which account for the majority of ovarian cancer deaths. While this proposal is focused on ovarian cancer, the methods are applicable to any cancer, and thus have broad significance. The consolidating theme of this proposal is to use deep sequencing and the novel analytic techniques described to study aspects of the serous ovarian cancer genome and transcriptome which have remained hidden due to limitations in technology or analytical methods. The experimental and analytical methods developed will be applicable to all tumor types and hence of broad relevance to the study of cancer.

描述(申请人提供)：复发性基因融合和内部串联复制是已知的最具肿瘤特异性的分子标记之一，可以提供潜在的治疗靶点。然而，除了少数值得注意的例外，在常见的癌症中还没有发现相对常见的复发基因融合，这种癌症通常有多个复杂的染色体重排，很难用传统的细胞遗传学方法进行分析。复杂的肿瘤核型使利用细胞遗传学鉴定基因融合变得困难，但提示产生融合或内部串联复制(ITDS)的反复重排可能是普遍存在的。这项建议旨在使用深度测序和所描述的新的分析技术来研究由于技术或分析方法的限制而仍然隐藏的浆液性卵巢癌基因组和转录组的某些方面，并测试个体内和个体间对肿瘤的选择压力。该建议的方面如下：1)进一步研究卵巢癌中基因重排的程度，重点是发现转录成RNA的局部重排；2)确定一组我最近发现在正常和致病人类细胞中相对高水平表达的新型循环转录本的组成；3)表征卵巢癌中的双分钟，结合生物信息学来确定其序列组成的重排，并进行统计分析，以确定肿瘤对其组成施加的进化压力。申请人在利用超高通量测序发现新的基因融合(ESRRA-C11orf20融合)以及为超高通量数据设计原创的严格的统计和生物信息学方法方面有着成功的记录。在高通量基因组技术和用于分析这些技术的统计方法的先驱帕特里克·O·布朗博士的指导下，申请者将继续职业发展和培训。该项目的第一个目标将在指导阶段实施，并将试行目标2和目标3的实验。K99/R00奖将支持申请者发展成为一名结合统计和实验方法研究癌症遗传学的独立研究员。 公共卫生相关性： 据估计，卵巢癌每年导致14万多名女性死亡，一旦出现临床症状，预后就会很差。发现真正的肿瘤特异性分子标志物或鉴定早期和选择性扩增可能对早期有效至关重要 检测浆液性肿瘤，这是卵巢癌死亡的主要原因。虽然这项建议的重点是卵巢癌，但这些方法适用于任何癌症，因此具有广泛的意义。 这项提议的巩固主题是使用深度测序和所描述的新的分析技术来研究由于技术或分析方法的限制而仍然隐藏的浆液性卵巢癌基因组和转录组的某些方面。开发的实验和分析方法将适用于所有类型的肿瘤，因此对癌症的研究具有广泛的相关性。