Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

摘要： 缺乏对基因变异如何影响介导TNBC攻击的分子机制的了解 而有效的抗肿瘤治疗对癌症治疗的进步构成了实质性的障碍。 目前的转基因小鼠模型(GEMM)缺乏遗传复杂性，因为小鼠 基于单一的近亲交配背景，这阻碍了对个体遗传变异的严格调查 可能会影响肿瘤的启动、进展或对治疗的反应。由于这一限制，临床前 模式通常无法很好地转化为影响患者护理。尽管人类研究已经确定了风险因素 对于用环境和遗传学方法发展TNBC，研究往往达不到要求，因为 无法控制变量或对足够多的个体进行抽样。为了解决这些限制，我们开创了一种 一种变革性的方法，建立了一种新的小鼠模型，具有健壮、可靠和可重复性 表型和基因组变异。我们系统地将C3(1)-T抗原(C3Tag)GEMM 被建立为类似于人类的基底状TNBC，进入BXD家族-最大和最具特征的 遗传参考种群。初步数据表明，BXD-TnBC F1等基因杂交种具有较大的 TNBC表型的严重程度不同，表明影响疾病的遗传修饰物。它的优势在于 BxD-TNBC杂交种是每个基因组都是可定义的和可复制的。使用尖端系统遗传学 和分子候选验证，我们将确定TNBC的遗传修饰因子。跨物种比较 通过公开获得的人类GWA和基因组数据库，将识别保守的、生物学上相关的和 有针对性的候选人，以产生高度影响和易于翻译的结果。我们假设 修饰基因和因果基因的交互作用控制着TNBC表型的异质性，并改变对 心理治疗。目标1将通过无偏见的方式识别和验证TNBC表型的新遗传修饰物 系统量化BXD-TNBC杂交种的TNBC严重性和遗传力。试点研究显示 影响TNBC患者生存的候选基因。AIM 2将识别和验证新的遗传修饰物 BXD-TNBC杂交种的治疗效果。最后，将肥胖和TNBC联系起来的基因贡献是 目前尚不清楚，这是一个问题，因为肥胖会加剧不良的BC结局，并减少 对患者的治疗效果。目标3将确定肥胖易感性加剧的遗传修饰因素 TNBC。利用我们团队的专业知识，总体目标是询问这种可复制的基因 使用已建立的成功战略来宣传人类风险的遗传学和应对 心理治疗。总之，缺乏针对TNBC的靶向治疗是一个巨大的未得到满足的临床需求。可交付成果 BXD-TNBC将定义易感基因、候选基因和构成其基础的分子网络 多种TNBC表型的变异。因此，产生的结果将是变革性的，具有很高的影响力，领先 用于识别改变TNBC中个体差异的异质性和网络的基因。

SUMMARY: The lack of understanding how genetic variants affect molecular mechanisms that mediate TNBC aggression and impact effective anti-tumor therapies poses a substantial obstacle to advancement in cancer therapies. Current genetically engineered mouse models (GEMMs) of TNBC lack genetic complexity because mice are on a single inbred background which impairs the rigorous investigation into how individual genetic variation might impact tumor initiation, progression, or response to therapy. Because of this limitation, pre-clinical models typically fail to translate well to impact patient care. Although human studies have identified risk factors for developing TNBC with both environmental and genetics approaches, studies often fall short due to the inability to control variables or sample enough individuals. To address these limitations, we have pioneered a transformative approach with the creation of a novel murine model with robust, reliable, and reproducible phenotypic and genomic variation. We systematically crossed the C3(1)-Tantigen (C3Tag) GEMM, well established to resemble human basal-like TNBC, into the BXD family - the largest and best characterized genetic reference population. Preliminary data demonstrate that BXD-TNBC F1 isogenic hybrids have greatly differing severity of TNBC phenotypes, indicating genetic modifiers that impact disease. The advantage of the BXD-TNBC hybrids is that every genome is defined and reproducible. Using cutting edge systems genetics and molecular candidate validation, we will identify genetic modifiers of TNBC. Cross-species comparisons with publicly available human GWAS and genomic databases will identify conserved, biologically relevant, and targetable candidates to yield highly impactful and readily translatable findings. We hypothesize that the interaction of modifier and causal genes govern the heterogeneity of TNBC phenotypes and alter response to therapy. Aim 1 will identify and validate novel genetic modifiers of TNBC phenotypes through unbiased systematic quantification of TNBC severity and heritability across BXD-TNBC hybrids. Pilot studies revealed candidate genes that impact patient survival in TNBC. Aim 2 will identify and validate novel genetic modifiers of therapeutic efficacy across BXD-TNBC hybrids. Last, the genetic contribution linking obesity and TNBC is currently unknown which is a problem because obesity exacerbates poor BC outcomes and reduces therapeutic efficacy in patients. Aim 3 will identify genetic modifiers of susceptibility to obesity exacerbated TNBC. Capitalizing upon our team’s expertise, the overall objective is to interrogate this replicable genetic resource using established successful strategies to inform on the genetics of human risk and response to therapy. In sum, the lack of targeted therapies for TNBC presents a great unmet clinical need. The deliverables of this novel BXD-TNBC will define susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple TNBC phenotypes. Results generated will thus be transformative with high impact, leading to the identification of genes modifying heterogeneity and networks underlying individual differences in TNBC.