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

总结： 缺乏对遗传变异如何影响介导TNBC攻击的分子机制的理解 有效的抗肿瘤治疗对癌症治疗的进展构成了实质性的障碍。 目前的TNBC基因工程小鼠模型（GEMM）缺乏遗传复杂性，因为小鼠是 在一个单一的近亲繁殖的背景，这损害了严格的调查，如何个人遗传变异， 可能影响肿瘤的发生、进展或对治疗的反应。由于这种局限性，临床前 模型通常不能很好地转化以影响患者护理。虽然人类研究已经确定了风险因素 对于用环境和遗传学方法开发TNBC，研究往往由于 无法控制变量或对足够的个体进行采样。为了解决这些局限性，我们开创了一种 通过建立一种新的小鼠模型， 表型和基因组变异。我们系统地将C3（1）-Tantigen（C3 Tag）GEMM杂交， 建立类似于人类基底细胞样TNBC，进入BXD家族-最大和最好的表征 遗传参考群体初步数据表明，BXD-TNBC F1同基因杂种具有很大的遗传多样性。 TNBC表型的不同严重程度，表明影响疾病的遗传修饰剂。的优势 BXD-TNBC杂交是每个基因组是定义和可重复的。利用尖端系统遗传学 和分子候选物验证，我们将鉴定TNBC的遗传修饰物。跨物种比较 与公开可用的人类GWAS和基因组数据库将确定保守的，生物学相关的， 有针对性的候选人，以产生高度影响力和易于翻译的结果。我们假设 修饰基因和致病基因的相互作用控制TNBC表型的异质性，并改变对TNBC的应答。 疗法目的1将通过无偏的方法鉴定和验证TNBC表型的新型遗传修饰剂。 在BXD-TNBC杂种中系统量化TNBC严重性和遗传性。试点研究显示， 影响TNBC患者生存率的候选基因。目标2将确定和验证新的遗传修饰剂， 在BXD-TNBC混合物中的治疗功效。最后，将肥胖和TNBC联系起来的遗传贡献是 目前尚不清楚这是一个问题，因为肥胖加剧了BC结果不佳， 患者的治疗效果。目标3将确定遗传修饰的易感性肥胖加剧 TNBC。利用我们团队的专业知识，总的目标是审问这个可复制的基因 资源使用既定的成功战略，以告知人类风险的遗传学和应对 疗法总之，TNBC靶向疗法的缺乏提出了很大的未满足的临床需求。可交付成果 这种新的BXD-TNBC将定义易感基因座，候选基因和分子网络， 多种TNBC表型的变异。因此，所产生的成果将具有变革性和高影响力， 涉及修饰TNBC个体差异的异质性和网络的基因的鉴定。

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.