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: 10524102
• 负责人: Luis Guillermo Carvajal Carmona
• 金额: $ 1.11万
• 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/10524102
• 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.

项目概要 胃癌（GC）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。 美国西班牙裔患者的死亡率和发病率落后于大多数其他癌症。 迫切需要进一步了解其病因，解决现有的研究空白将有助于提高准确性。 在最近的一项研究中，我们发现，预防和治疗将改善生存结果和差异。 同源重组 (HR) 修复基因 PALB2、BRCA1 和 RAD51C 的种系突变 多个 GC 患者，表明 HR 途径在这些患者的肿瘤风险中很重要。 HR 缺陷 (HRD) 突变特征，据报道约 7% 的散发性非突变特征 从统计学上看，我们未发表的西班牙裔白人 (NHW) 肿瘤患病率较高。 具有 HRD 表型的胃肿瘤（19%）。这些最新发现对于精准 GC 具有双重重要性。 HR 基因检测现在可以考虑通过种系 HR 基因突变检测进行预防 HRD 肿瘤患者可能会受益于 PARP 抑制剂，为唯一的其他药物提供了一个有希望的选择 我们计划的长期目标是产生可用于 GC 治疗的分子引导疗法。 改善 GC 结果和差异的知识 该应用程序的目标是识别新的。 GC 基因并表征西班牙裔胃肿瘤的基因组、临床病理学和风险概况 我们的假设是，HR 通路富含 GC 风险变异。 在目标 1 中，我们将鉴定西班牙裔和 HRD GC 具有独特的基因组谱。 使用所有 HR 通路基因的靶向测序，对 384 名西班牙裔家族性早发患者进行了研究。 我们的分析将侧重于确定种系 HR 基因突变携带者的主要临床特征 在目标 2 中，我们将进行外显子组测序。 对来自 300 名西班牙裔 GC 患者的配对肿瘤/正常样本进行拷贝数分析 在拉丁美洲的一项多中心研究中，基因组数据将用于识别可能的新型 GC 驱动因素。 针对特定人群，估计先前已知的 GC 分子亚型和驱动基因的流行率 在 NHW 中鉴定并进行分子表型与广泛的临床和 在目标 3 中，我们将从已发表的研究中汇编 HRD 数据。 从本研究中确定这种“可成药”的主要临床、组织学和危险因素特征 拟议的研究建立在新发现的 HR 途径 GC 基因的广泛试验数据的基础上。 将利用我们优秀且特征明确的患者资源和样本，其中包括高风险 这项研究的重点是显着的癌症差异，我们将生成重要的数据。 了解GC基因组学和病因学并开发分子指导疗法。