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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.

项目总结/摘要癌基因突变编码的蛋白质具有增强适应性的功能获得性生物学特性。从历史上看，癌基因中的杂合突变被认为足以诱导癌症的发生或发展。促进癌症进展。然而，致癌驱动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，明白我们最近发现，KRAS G12 D拷贝数增加和随后的WT丢失，白血病中的KRAS等位基因以增加MAP激酶途径为代价导致竞争适应性增加依赖在随后的初步研究中，我们发现针对功能获得性的接合性改变致癌突变在癌症演变过程中经常被选择，影响这些发现暗示了WT等位基因对突变癌基因的更广泛的生长抑制作用。功能，并强调了前瞻性地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接合性的变化。然而，如果没有原则性的方法，为了表征致癌突变等位基因不平衡的程度和意义，我们的研究中的差距对癌基因生物学和治疗的理解将会拓宽。因此，我们建议功能和翻译基因组研究，以检验突变癌基因接合性的变化决定不同肿瘤的假设癌症的生物学和治疗敏感性。在目标1中，我们前瞻性地利用了70，000人的队列测序的癌症患者与详细的临床和治疗注释相关联，以确定患病率，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了治疗敏感性的预测生物标志物，并为科学研究创造了公共资源。社区，以促进更广泛的机制研究突变癌基因接合性。我们的初步数据显示竞争性适应性导致大约一半的RAS突变型肿瘤中WT RAS丢失。因此在目的2：我们利用单细胞表征的进展来定义这种系列遗传进化的起源，建立独立产生的靶向突变体的分子变化的时序和适应性增益和从KRAS突变型癌症患者的转移性肿瘤分离的单细胞中的野生型KRAS等位基因。最后，在目标3中，我们使用工程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）基因的常见缺失WT等位基因在ESR 1突变型ER+中的抑制作用转移性乳腺癌，第一次将这种现象扩展到突变型RAS之外。总之，拟议的研究试图建立突变癌基因的变化的生物学和临床意义，接合性通过与我们的机构临床测序计划的整合，我们预计，这些发现将改变临床试验的设计，并改进广泛适用的治疗敏感性生物标志物。在分子定义的癌症患者群体中。