Genetic studies of homologous recombination deficiency in hispanic gastric cancer

项目摘要 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。 美国西班牙裔的死亡率和发病率。精确的GC医学落后于大多数其他癌症， 迫切需要进一步了解其病因。解决现有的研究差距将促进精确性 预防，治疗，并将改善生存结果和差距。在最近的一项研究中，我们发现 同源重组（HR）修复基因PALB 2、BRCA 1和RAD 51 C的种系突变， 多个GC患者，提示HR途径在GC风险中很重要。这些患者的肿瘤 HR缺陷（HRD）突变特征，在约7%的散发性非- 西班牙裔白色（NHW）肿瘤。有趣的是，我们未发表的西班牙裔数据表明， 胃肿瘤伴HRD表型（19%）。这些最新发现在精密GC中具有双重重要性 作为HR基因检测的药物，现在可以考虑通过生殖系HR基因突变检测进行预防 HRD肿瘤患者可能受益于PARP抑制剂，为唯一的其他选择提供了一个有希望的选择。 分子引导疗法可用于GC治疗。我们项目的长期目标是 改善全球治理成果和差距。本申请的目的是确定新的 GC基因，并描述西班牙裔胃肿瘤的基因组、临床病理学和风险特征， 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具有独特的基因组图谱。在目标1中，我们将鉴定 384例西班牙裔家族性和早发性患者，使用所有HR途径基因的靶向测序。 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 估计HR基因突变率和突变率。在目标2中，我们将进行外显子组测序， 对来自300名西班牙裔胃癌患者的配对肿瘤/正常样本进行拷贝数分析， 在拉丁美洲的多中心研究中。基因组数据将用于鉴定可能是 人群特异性，以估计已知GC分子亚型和驱动基因的患病率， 在NHW中鉴定，并进行分子表型与广泛的临床和 所有这些样本中的风险因素数据。在目标3中，我们将从已发表的研究中汇编人力资源开发数据， 从目前的研究，以确定主要的临床，组织学和危险因素的特点，这种“药物” 肿瘤类型这项研究建立在新发现的HR途径GC基因的广泛试点数据基础上。我们 我们将利用我们优秀和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。这项研究的重点是一个显着的癌症差异，我们将产生数据， 了解GC基因组学和病因学以及分子指导疗法的发展。

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 Interestingly, our unpublished data in Hispanics suggest a higher prevalence of gastric tumors with the HRD phenotype (19%).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.