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

DCP假设，在Lynch综合征中观察到的复发性移码突变也会发生在体质性错配修复缺陷（CMMRD）中，并且DCP正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正在使用来自Pms2突变小鼠模型（GEMM）的正常粘膜、肿瘤组织、血液（cfDNA和RNA）和粪便DNA样本中的一组约30个单核苷酸重复基因座进行靶向下一代测序。这将建立小鼠模型与可用的Lynch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中进行癌症预防功效测试。 下一阶段需要收集人体样本的生物标本。将使用约120个单核苷酸重复基因座的扩展组对采集的标本进行测序。根据研究结果，将考虑创建一种新的移码疫苗或扩大计划中的林奇综合征癌症预防试验，以包括CMMRD，特别是高风险的因纽特人队列。 将在DCP资助的CIPL实验室可分割工作单元（目前是NCI操作任务指令75N91020F00003的一部分）下，对该生物标本采集所获得的人体样本进行测序文库生成、分析和数据报告的下游工作。

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).