Defining the impact of mutant oncogene zygosity

定义突变癌基因接合性的影响

基本信息

批准号：
10362576
负责人：
Sarat Chandarlapaty
金额：
$ 39.68万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362576
关键词：
Address Advanced Malignant Neoplasm Alleles Allelic Imbalance BRAF gene Biochemical Biological Biological Markers Biological Process Biological Response Modifier Therapy Biology Breast Cancer Patient Cancer Patient Cells Chronology Clinical Clinical Treatment Clinical Trials Design Communities Computing Methodologies DNA copy number Data Data Analyses Dependence Diagnosis Disease Progression ERBB2 gene ESR1 gene Estrogen Receptors Evolution FDA approved Fostering Genes Genetic Genomic approach Genomics Goals Growth Human Investigation KRAS oncogenesis KRAS2 gene KRASG12D Link Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic breast cancer Methods Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Molecular Mutation Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Patients Phenotype Physicians Population Prevalence Property Proteins Receptor Gene Research Resources Role Sampling Sum System Testing Therapeutic Time Tumor Biology Tumor Suppressor Proteins cancer genome cancer initiation cancer type cell free DNA cellular engineering clinical application clinical sequencing clinically significant co-clinical trial cohort colon cancer patients cost dosage driver mutation fitness flexibility functional genomics gain of function gain of function mutation genetic evolution innovation insight leukemia multidisciplinary mutant novel therapeutic intervention patient derived xenograft model precision oncology predictive marker prognostic prospective response biomarker single cell analysis stoichiometry translational genomics treatment optimization treatment response tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Mutations in oncogenes encode proteins with gain-of-function biological properties that enhance fitness. Historically, heterozygous mutations in oncogenes have been viewed as sufficient to induce cancer initiation or promote cancer progression. However, oncogenic driver mutations often co-exist with extensive genomic gains and losses. Yet, the interplay between these two fundamental properties of cancer genomes is poorly understood. We recently showed that increased KRAS G12D copy number and subsequent loss of the WT KRAS allele in leukemias leads to increased competitive fitness at the cost of increased MAP kinase pathway dependence. In subsequent preliminary studies, we showed that zygosity changes targeting gain-of-function oncogenic mutations are frequently selected for during cancer evolution and have prognostic and therapeutic implications. These findings allude to broader growth suppressive effects of the WT allele on mutant oncogene function and underscore the potential clinical importance of prospectively identifying for physicians and patients changes in mutant oncogene zygosity within the context of precision oncology. Yet, without principled methods for characterizing the extent and significance of oncogenic mutant allele imbalance, the gap in our understanding of oncogene biology and therapy will widen. We therefore propose functional and translational genomic investigations to test the hypothesis that changes in mutant oncogene zygosity dictates distinct tumor biology and therapeutic sensitivities in cancer. In Aim 1, we leverage a cohort of 70,000 prospectively sequenced cancer patients linked to detailed clinical and treatment annotation to establish the prevalence and mechanisms of oncogenic mutant allele imbalance. We will identify the degree to which allelic imbalance represents a predictive biomarker of therapeutic sensitivity and create a public resource for the scientific community to foster broader mechanistic studies of mutant oncogene zygosity. Our preliminary data indicates that competitive fitness drives the loss of WT RAS in approximately half of all RAS-mutant tumors. Thus, in Aim 2 we utilize advances in single-cell characterization to define the origins of such serial genetic evolution, establishing the chronology and fitness gains of independently arising molecular changes targeting the mutant and wildtype KRAS alleles in single cells isolated from metastatic tumors of KRAS-mutant cancer patients. Finally, in Aim 3 we use engineered cellular systems and patient-derived xenografts to study the tumor suppressive effect of the commonly deleted WT allele of the estrogen receptor (ER) gene in ESR1-mutant ER+ metastatic breast cancers, extending this phenomenon beyond mutant RAS for the first time. In sum, the proposed studies seek to establish the biological and clinical significance of changes to mutant oncogene zygosity. Through the integration with our institutional clinical sequencing initiative, we anticipate that our findings will alter the design of clinical trials and refine broadly applicable biomarkers of therapeutic sensitivity in molecularly defined populations of cancer patients.

项目摘要/摘要致癌基因的突变编码具有功能获得生物学特性的蛋白质，以增强适应性。从历史上看，肿瘤基因中的杂合突变被认为足以诱导癌症起源或促进癌症进展。但是，致癌驱动器突变通常与广泛的基因组增益共存和损失。然而，癌症基因组的这两个基本特性之间的相互作用很差理解。我们最近表明，KRAS G12D副本编号和随后的WT损失增加白血病中的KRAS等位基因导致竞争性健身增加，而MAP激酶途径增加依赖。在随后的初步研究中，我们表明了靶向功能获得的合格变化在癌症进化过程中经常选择致癌突变，并具有预后和治疗性含义。这些发现暗示了WT等位基因对突变癌基因的更广泛的生长抑制作用功能并强调了前瞻性识别医生和患者的潜在临床重要性在精确肿瘤学的背景下，突变癌基因的合并的变化。但是，没有原则的方法为了表征致癌突变体等位基因不平衡的程度和意义，我们的差距了解癌基因生物学和治疗将扩大。因此，我们提出功能和翻译基因组研究以检验突变性癌基因合格性变化的假设决定了独特的肿瘤癌症的生物学和治疗敏感性。在AIM 1中，我们利用了70,000的队列测序的癌症患者与详细的临床和治疗注释有关，以确定患病率和致癌突变等位基因失衡的机制。我们将确定等位基因失衡的程度代表治疗敏感性的预测生物标志物，并为科学创造公共资源社区以促进突变癌基因的更广泛的机理研究。我们的初步数据指示这种竞争性健身驱动了大约一半RAS突变肿瘤中WT RAS的损失。因此，在 AIM 2我们利用单细胞表征的进步来定义这种串行遗传进化的起源，建立针对突变体的分子变化的年表和适应性增长从KRAS突变癌患者转移性肿瘤分离的单细胞中的WildType Kras等位基因。最后，在AIM 3中，我们使用工程的细胞系统和患者来源的异种移植物来研究肿瘤雌激素受体（ER）基因的常见WT等位基因在ESR1突变剂ER+中的抑制作用转移性乳腺癌，首次将这种现象扩展到突变的RAS之外。总而言之拟议的研究旨在建立变化对突变体果仁的生物学和临床意义 Zygosity。通过与我们的机构临床测序计划的整合，我们预计我们的调查结果将改变临床试验的设计，并改进了治疗敏感性的广泛适用的生物标志物在分子定义的癌症患者中。