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: 10411392
• 负责人: Luis Guillermo Carvajal Carmona
• 金额: $ 7.26万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411392
• 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; Hispanics; 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/antagonist; 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.

项目摘要 胃癌（GC）是癌症相关死亡的第三个原因，是与癌症相关的主要原因 美国西班牙裔的死亡率和发病率。精密GC药物落后于大多数其他癌症，有 迫切需要进一步了解其病因。解决现有的研究差距将有助于精确 预防，治疗并将改善生存结果和分布。在最近的一项研究中，我们确定了 同源重组（HR）修复基因PALB2，BRCA1和RAD51C中的种系突变 多个GC患者，表明HR途径在GC风险中很重要。这些患者的肿瘤有 HR缺乏（HRD）突变签名，该特征已在约7％的零星非 - 中报道 西班牙裔白色（NHW）肿瘤。有趣的是，我们在西班牙裔中未发表的数据表明， HRD表型的胃肿瘤（19％）。这些最近的发现在精确GC中具有双重重要性 现在可以通过种系HR基因突变测试来考虑医学作为人力资源基因测试 HRD肿瘤患者可能会受益于PARP抑制剂，为唯一的其他人提供承诺选择 分子引导的疗法可用于GC治疗。我们计划的长期目标是生成 改善GC结果和差异的知识。此应用程序的目标是确定新的 GC基因并表征西班牙胃肿瘤的基因组，临床病理和风险特征 尤其是胃HRD肿瘤。我们的假设是HR途径富含GC风险变体 西班牙裔和HRD GC具有独特的基因组概况。在AIM 1中，我们将确定在 使用所有人力资源途径基因的靶向测序，有384例西班牙裔患者和早期发作的患者。 我们的分析将着重于确定种系HR基因突变载体的主要临床特征 并估计HR基因突变的患病率和外观。在AIM 2中，我们将进行外显子组测序 和招募300名西班牙裔GC患者的配对肿瘤/正常样品的副本编号分析 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是的新型GC驱动因素 人群特异性，以估算以前已知的GC分子亚型和驱动器基因的流行率 在NHWS中确定，并在分子表型与广泛的临床和 所有这些样本中可用的风险因素数据。在AIM 3中，我们将从已发表的研究中编译HRD数据， 从本研究来确定此“可药”的主要临床，组织学和危险因素特征 肿瘤类型。拟议的研究基于新发现的HR途径GC基因的广泛试点数据。我们 将利用我们出色且特征良好的患者资源和样本，其中包括高风险 西班牙裔人口。这项研究侧重于巨大的癌症差异，我们将生成有关的数据。 了解GC基因组学和病因以及分子引导疗法的发展。