Network Group Integrated Translational Science Centers Application

描述（由申请人提供）：在靶向治疗时代，实验室研究是癌症临床试验不可或缺的组成部分。连接治疗和结果的最强大的技术之一是使用大规模平行测序（MPS）询问核酸（DNA或RNA）的测定。实施基于核酸的方法以检测与种系相比的体细胞序列改变（“突变”）或结构变异，包括染色体的异常融合、正常DNA序列的丢失（“缺失”）或序列重复（“扩增”）。或者，测序分析可以靶向非癌细胞的DNA，以解决不同的问题，包括记录完整的参考基因组，家族性癌症综合征的基因分型，以及具有治疗重要性的药物代谢酶的基因分型。在该提议中提出了一种高度靶向的捕获方法（使用数百个通路基因）。FDA将从拨款的第一天起，以符合监管要求的方式提供高样本量的临床测序。作为从冷冻和石蜡包埋材料生产基于人类RNA的癌症检测试剂盒（包括微阵列、RNA测序和靶向RNA定量）的世界领导者，检测试剂盒在合规环境中提供。在监管过程中提供专业知识至关重要，以便前瞻性地提供NGS检测，用于治疗决策和患者随机化。本提案的目的1和2涉及提供符合FDA和CAP的机制，用于对多机构合作组临床试验提供的冷冻或石蜡包埋样本进行高通量RNA和DNA测序。RNA测序将提供3种格式：RNA-Seq、NanoString和G-rtPCR，以实现全面的RNA测序和廉价的靶向RNA分析。DNA测序将通过下一代测序以及NanoString的定量DNA测量提供整个外显子组和靶向捕获。第三个目标是开发和提供监管服务核心，以加快FDA和CLIA合规检测的批准，这些检测旨在用于前瞻性临床试验。

DESCRIPTION (provided by applicant): In the era of targeted therapy, laboratory studies are an integral component of cancer clinical trials. Among the most powerful techniques connecting therapies and outcomes are assays which interrogate nucleic acid (DNA or RNA) using massively parallel sequencing (MPS). Nucleic acid-based approaches are implemented to detect either somatic sequence alterations ("mutations") compared to germline or structural variation including abnormal fusion of chromosomes, loss of normal DNA sequences ("deletions") or sequence duplications ("amplifications"). Alternatively, sequencing assays can target DNA from noncancerous cells to address different questions, including documenting the intact reference genome, genotyping of familial cancer syndromes, and genotyping of drug metabolizing enzymes of therapeutic importance. A highly targeted capture approach (using hundreds of pathway genes) is proposed in this proposal. UNC will provide high sample volume clinical sequencing in a regulatory compliant manner from day one of the grant. As a world leader in the production of human RNA-based cancer assays from both frozen and paraffin-embedded material, including microarrays, RNA sequencing, and targeted RNA quantification, assays are offered within a compliant setting. It is vital to provide expertise in the regulatory process to offer NGS assays prospectively for the purpose of treatment decision-making and patient randomization. Aims 1 and 2 of this proposal involve providing an FDA- and CAP- compliant mechanism for high sample throughput RNA and DNA sequencing from frozen or paraffin-embedded samples provided from multi-institutional cooperative group clinical trials. RNA sequencing will be offered for 3 formats, RNA-Seq, NanoString, and G- rtPCR, to allow both comprehensive RNA sequencing and inexpensive targeted RNA profiling. DNA sequencing will be offered for both whole exome and targeted capture by next generation sequencing as well as quantitative DNA measures by NanoString. The third aim is to develop and provide a regulatory services core to expedite approval for both FDA and CLIA compliant assays designed to be implemented for prospective clinical trials.