PMS2 MUTATIONS PROJECT: BIOSPECIMENS PROCUREMENT FOR CHARACTERIZATION FROM HIGH-RISK POPULATION OF CANADIAN INUIT

DCP假设，就像在Lynch综合征中观察到的那样，反复发生的帧移动突变也将发生在宪法错配修复缺陷(CMMRD)中，并且DCP已经在开发的新抗原疫苗策略和试剂将与CMMRD综合征的癌症预防相关。 为了验证这一假设，DCP正在使用一组约30个单核苷酸重复基因座进行有针对性的下一代测序，这些基因座来自PMS2突变小鼠模型(GEMM)的正常黏膜、肿瘤组织、血液(cfDNA和RNA)和粪便DNA样本。这将建立小鼠模型与可用的林奇综合征疫苗的相关性。如果目前的疫苗是相关的，它们将在GEMM中进行癌症预防效果测试。 下一阶段需要收集人体样本的生物制品。收集的样本将使用一个由大约120个单核苷酸重复基因座组成的扩展小组进行测序。根据结果，将考虑创建一种新的移帧疫苗或扩大计划中的林奇综合征癌症预防试验，以包括CMMRD，特别是高风险因纽特人队列。 为这次生物检疫采集获得的人类样本生成测序库、分析和数据报告的下游工作将在DCP资助的CIPL实验室的可分割工作单元(目前是NCI操作任务令75N91020F00003的一部分)下进行。

DCP hypothesizes that recurrent frame-shift mutations, as observed in Lynch Syndrome, will also occur in Constitutional Mismatch Repair Deficiency (CMMRD) and that the neoantigen vaccine strategy and reagents already under development by DCP will be relevant to cancer prevention in CMMRD Syndrome. To test this hypothesis, DCP is conducting targeted next generation sequencing using a panel of ~30 mononucleotide repeat loci in samples of normal mucosa, tumor tissue, blood (cfDNA and RNA), and fecal DNA from the Pms2 mutant mouse model (GEMM). This will establish the relevance of the mouse model to the available Lynch Syndrome vaccines. If the current vaccines are relevant, they will be tested for cancer preventive efficacy in the GEMM. A biospecimen collection of human samples is needed for the next stage. Specimens from the collection will be sequenced using an expanded panel of ~120 mononucleotide repeat loci. Based on the results, consideration will be given to creation of a new frame-shift vaccine or expanding planned Lynch Syndrome cancer prevention trials to include CMMRD and particularly the high-risk Inuit cohort. The downstream work for generation of sequencing libraries, analysis, and data reporting for human samples obtained for this biospecimen collection will be performed under the DCP-funded severable Unit of Work for the CIPL lab (currently part of NCI Operational Task Order 75N91020F00003).