Genetic studies of homologous recombination deficiency in hispanic gastric cancer

西班牙裔胃癌同源重组缺陷的遗传学研究

• 批准号: 10425289
• 负责人: Luis Guillermo Carvajal Carmona
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425289
• 关键词: Abbreviations; Address; Age; Alcohol consumption; BRCA1 gene; Body Size; CDH1 gene; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Clinical; DNA; Data; Development; Diagnosis; Diffuse gastric cancer; E-Cadherin; Early Diagnosis; Early treatment; Etiology; Family Cancer History; Gene Mutation; Genes; Genetic; Genetic Research; Genetic study; Genomics; Germ-Line Mutation; Goals; Helicobacter Infections; High Prevalence; Hispanic; Hispanic Populations; Histologic; Histology; Human Herpesvirus 4; Inherited; Knowledge; Latin America; Location; Malignant Neoplasms; Medicine; Microsatellite Repeats; Minority; Molecular; Morbidity - disease rate; Multicenter Studies; Mutate; Mutation; Not Hispanic or Latino; Oncogenes; Outcome; PALB2 gene; Pathologic; Pathway interactions; Patients; Penetrance; Phenotype; Population; Prevalence; Prevention; Publishing; RAD51C gene; Recurrence; Reporting; Research; Resources; Risk; Risk Factors; SNP array; Sampling; Single Nucleotide Polymorphism; Smoking Status; Stomach; Stomach Neoplasms; Testing; The Cancer Genome Atlas; Time; base; cancer genome; cancer genomics; cancer health disparity; cancer risk; cancer survival; cancer therapy; clinical risk; cohort; driver mutation; early onset; exome sequencing; gastric cancer prevention; gene repair; genetic testing; genomic data; genomic profiles; high risk; homologous recombination; improved; individualized prevention; inhibitor; male; malignant stomach neoplasm; molecular phenotype; molecular subtypes; mortality; mutation carrier; novel; programs; recruit; risk variant; sex; survival disparity; survival outcome; targeted sequencing; tumor

PROJECT SUMMARY Gastric cancer (GC) is the third worldwide cause of cancer-related death and a leading cause of cancer related mortality and morbidity in U.S. Hispanics. Precision GC medicine lags behind most other cancers and there is an urgent need to further understand its etiology. Addressing existing research gaps will facilitate precision prevention, treatment, and will improve survival outcomes and disparities. In a recent study, we identified germline mutations in the homologous recombination (HR) repair genes PALB2, BRCA1 and RAD51C in multiple GC patients, suggesting that the HR pathway is important in GC risk. Tumors from these patients have a HR-deficient (HRD) mutational signature, a signature that has been reported in ~7% of sporadic non- Hispanic white (NHW) tumors. Interestingly, our unpublished data in Hispanics suggest a higher prevalence of gastric tumors with the HRD phenotype (19%). These recent findings have dual importance in precision GC medicine as HR gene testing can now be considered in prevention through germline HR gene mutation testing and patients with HRD tumors may benefit from PARP inhibitors, providing a promising option to the only other molecularly-guided therapies available for GC treatment. The long-term goal of our program is to generate knowledge for improving GC outcomes and disparities. The objectives of this application are to identify new GC genes and to characterize the genomic, clinico-pathological and risk profile of Hispanic gastric tumors and of gastric HRD tumors in particular. Our hypotheses are that the HR pathway is enriched with GC risk variants and that Hispanic and HRD GCs have unique genomic profiles. In Aim 1, we will identify germline mutations in 384 familial and early-onset patients of Hispanic origin using targeted sequencing of all HR pathway genes. Our analyses will focus on identifying the main clinical characteristics of germline HR gene mutation carriers and on estimating HR gene mutation prevalence and penetrance. In Aim 2, we will conduct exome sequencing and copy number analyses of paired tumor/normal samples from 300 Hispanic GC patients that were recruited in a multi-center study in Latin America. The genomic data will be used to identify novel GC drivers that may be population-specific, to estimate the prevalence of known GC molecular subtypes and driver genes previously identified in NHWs and to carry out comparisons between molecular phenotypes and the extensive clinical and risk factor data available in all these samples. In Aim 3, we will compile HRD data from published studies and from the present study to identify the main clinical, histological and risk factor characteristics of this “druggable” tumor type. The proposed study builds on extensive pilot data of newly-discovered HR pathway GC genes. We will capitalize on our excellent and well-characterized patient resources and samples, which include a high-risk Hispanic population. This study focuses on a significant cancer disparity and we will generate data essential for understanding GC genomics and etiology and for the development of molecularly-guided therapies.

项目总结 摘要胃癌是全球第三大癌症相关死亡原因，也是癌症相关死亡的主要原因。 美国拉美裔美国人的死亡率和发病率。精密GC医学落后于大多数其他癌症，而且有 迫切需要进一步了解其病因。解决现有的研究差距将促进精确度 预防、治疗，并将改善生存结果和差异。在最近的一项研究中，我们发现 人类同源重组(HR)修复基因PALB2、BRCA1和RAD51C的种系突变 多个GC患者，提示HR通路在GC风险中起重要作用。这些患者的肿瘤 一种HR缺乏(HRD)突变签名，据报道，这种签名在~7%的散发性非 西班牙裔白人(Nhw)肿瘤。有趣的是，我们在拉美裔美国人中未发表的数据表明， HRD表型的胃肿瘤(19%)。这些最新发现在精密气相色谱中具有双重重要性 作为HR基因检测的医学现在可以被认为是通过生殖系HR基因突变检测进行预防 患有HRD肿瘤的患者可能受益于PARP抑制剂，为唯一的其他患者提供了一个有希望的选择 分子导向疗法可用于GC治疗。我们计划的长期目标是产生 改善GC结果和差距的知识。此应用程序的目标是识别新的 GC基因，并分析拉美裔胃肿瘤的基因组、临床病理和风险特征 尤其是胃HRD肿瘤。我们的假设是HR通路富含GC风险变异体 而且西班牙裔和HRD GC有独特的基因组图谱。在目标1中，我们将在 使用所有HR途径基因的靶向测序，对384名西班牙裔家族性和早发性患者进行研究。 我们的分析将集中于确定生殖系HR基因突变携带者的主要临床特征 以及估计HR基因突变的患病率和外显率。在目标2中，我们将进行外显子组测序 来自300名西班牙裔GC患者的成对肿瘤/正常样本的拷贝数分析 在拉丁美洲的一项多中心研究中。基因组数据将被用来识别可能是 人群特异性，以估计先前已知的GC分子亚型和驱动基因的流行程度 并在分子表型和广泛的临床和 所有这些样本中都有风险因素数据。在目标3中，我们将从已发表的研究中收集人力资源开发数据，并 从目前的研究中找出这种“可服药”的主要临床、组织学和危险因素特征 肿瘤类型。这项拟议的研究建立在新发现的HR途径GC基因的广泛先导数据的基础上。我们 将利用我们优秀且具有良好特性的患者资源和样本，其中包括高风险 西班牙裔人口。这项研究的重点是显著的癌症差异，我们将生成必要的数据 了解GC基因组学和病因学以及分子导向疗法的发展。