Towards an inclusive genomic risk classification for acute myeloid leukemia (AML)

A.项目总结 急性髓系白血病(AML)是成人最常见的急性白血病。分子特征，如 细胞遗传学和体细胞突变是风险分层的基本组成部分；用于日常临床 确定治疗方式和强度的做法。我们对复发遗传性急性髓细胞白血病相关知识的认识 特征、生存关联、随后的遗传风险分类和临床实践由大型- 在过去十年中，对中欧血统的患者进行了大规模基因组研究。因此， 目前的临床实践是基于这样的假设，即已经进行了充分的测试，并且 遗传背景不应影响已知的与急性髓细胞白血病相关的遗传和基因组格局和基因 与治疗反应和/或驱动急性髓系白血病发生有关。然而，我们的出版和初步 数据显示，血统不仅影响已知的AML相关基因的频率和影响 突变，但也包括基因中的多个重复性变异--到目前为止与急性髓系白血病的发生无关。我们 假设：a)已知的急性髓细胞白血病相关驱动因素可能具有不同的预后意义，并且可能需要 根据血统在临床风险分类中进行调整，以及b)一些未被识别的分子 这些特征是AML发生和/或治疗耐药的祖先相关驱动因素。我们建议延长我们的 对AML基因组和基因组学的初步研究，以提供关于频繁突变的统计置信度 基因，以及AML患者更具包容性的分子调整风险和治疗分层。接下来，我们 将把重点放在NPM1c上，这是一种在中欧AML患者中提供有利结果的基因 祖先，但其他祖先的结果很差。我们将使用尖端的单细胞多组分析来 从潜在的驱动突变中勾勒出旁观者克隆突变，然后我们将从生物学上测试它们在 克隆性/白血病干细胞频率和治疗反应。我们希望提供一个包容性的 描述AML的遗传和基因组格局，识别那些具有预后意义的变异 意义，并提供了迄今为止未被认识到的治疗反应和生存驱动因素的范例。 总体目标是使精确的肿瘤学方法能够适应潜在的影响 人类遗传学。

A. PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common adult acute leukemia. Molecular features such as cytogenetics and somatic mutations are essential components of risk stratification; used in daily clinical practice to determine treatment modality and intensity. Our knowledge of recurrent genetic AML-associated features, survival associations, subsequent genetic risk classification and clinical practice is informed by large- scale genomic studies performed over the past decade on patients of Central-European ancestry. Thus, current clinical practice is predicated on the supposition that adequate testing has been performed, and that genetic background should not affect the known AML-associated genetic and genomic landscape and genes that associate with treatment response and/or that drive AML-genesis. However, our published and preliminary data reveal that ancestry affects not only the frequencies and impact of known AML-associated gene mutations, but also multiple recurrent variants in genes thus-far not implicated in AML-genesis. We hypothesize that: a) known AML-associated drivers may carry different prognostic significance and might need to be adjusted in clinical risk classifications depending on ancestry, and b) some unrecognized molecular features are ancestry-associated drivers of AML-genesis and/or therapy resistance. We propose to extend our initial studies of AML genomes and genomics to provide statistical confidence around frequently mutated genes, and a more inclusive molecularly-adjusted risk and treatment stratification for AML patients. Next, we will focus on NPM1c, a genotype which confers favorable outcome in AML patients with Central-European ancestry, but poor outcomes in other ancestries. We will use cutting-edge single-cell multiomic assays to delineate bystander clonal mutations from potential driver mutations, then we will biologically test their role in clonality/leukemia-stem-cell frequency and treatment response. We expect to provide an inclusive characterization of the genetic and genomic landscape of AML, identify those variants with prognostic significance, and provide exemplars of here-to-fore unrecognized drivers of treatment response and survival. The overall goal is to enable precision oncology approaches which accommodate the effects of underlying human genetics.