Integrated genomic analysis of racial disparities in endometrial cancer

描述（由申请人提供）：尽管非裔美国人（AA）妇女子宫内膜癌的发病率低于白人（C）妇女，但美国子宫内膜癌生存率存在显著的种族差异，黑人的生存率比白人低30%。单独的社会人口学因素不能解释这种差异，因为当对黑人和白色妇女按阶段和生物攻击性（即，II型）子宫内膜肿瘤。子宫浆液性乳头状癌（USC）是子宫内膜癌中最具侵袭性的组织学亚型。这种子宫内膜癌的变异在AA女性中的发生率是C女性的三倍。基于我们最近发表的关于USC遗传景观的数据，表明遗传和生物学因素可能是生存率种族差异的基础，最终目标是开发新的，更特异性和更有效的治疗方法来诊断和治疗AA女性中常见的USC，我们提出以下建议：目的1：通过全外显子组测序确定200个USC样本中的驱动突变候选者、杂合性丢失（洛）模式和拷贝数变异（CNV），并使用生物信息学策略对AA与C肿瘤之间的遗传差异进行系统评估，目标二：评估USC与AA和C中的miRNA和mRNA表达差异，并对影响USC不同组中疾病的途径进行下游分析（即，c-erbB 2 + vs阴性和PIK 3CA和CCNE 1突变体vs野生型）和目的3：使用原代USC细胞系和靶向试剂（包括曲妥珠单抗和T-DM 1（即，靶向c-erbB 2的mAb）、AZD 8055、GDC-0980和CYC 065（即，a mTOR/PI 3 K/CDK抑制剂）。这一建议包括第一次综合分析 AA开发的USC与C女性相比的基因组差异，以及目前鉴定的差异表达基因的验证，这些基因携带关键驱动突变，作为少数USC治疗的新靶点。相关性定义和功能验证的关键驱动突变和下游信号通路的差异活跃在AA妇女窝藏USC可用于指导新的，高效的靶向治疗对这些高度侵袭性肿瘤，因此，可能有直接的临床相关性少数民族的健康。

DESCRIPTION (provided by applicant): Although the incidence of endometrial cancer in African-American (AA) women is lower than in Caucasian (C) women, a striking racial disparity exists in endometrial cancer survival rates in the United States, with blacks having up to 30% worse survival rates than whites. Socio-demographic factors alone cannot account for this difference because differences in survival still occur when analyses are adjusted for black and white women by stage and by biologically aggressive (i.e., Type II) endometrial tumors. Uterine serous papillary carcinoma (USC), represents the most aggressive histologic subtype of endometrial cancer. This variant of endometrial carcinoma is up to three fold more frequent in AA women when compared to C women. On the basis of our recently published data on the genetic landscape of USC suggesting that genetic and biologic factors may underlie the racial disparity in survival rates and with the ultimate goal to develop novel, more specific and more effective treatment modalities for the diagnosis and therapy of USC so common in AA women, we propose the following: Aim 1: Identify through whole exome sequencing driver mutation candidates, loss of heterozygosity (LOH) patterns and copy number variations (CNV) in 200 USC samples and use bioinformatics strategies to perform a systematic assessment of genetic differences between AA vs C tumors, Aim 2: Evaluate miRNAs and mRNA expression differences in USC from AA and C and perform downstream analysis of pathways influencing disease in different groups of USC (i.e., c-erbB2+ vs negative and PIK3CA and CCNE1 mutants vs wild type) and Aim 3: Evaluate the biochemical properties of a subset of novel PIK3CA mutations and validate the c-erbB2/PIK3CA and CCNE1 pathways as novel targets for USC treatment using primary USC cell lines and targeted agents including trastuzumab and T-DM1 (i.e., mAbs targeting c-erbB2), AZD8055, GDC-0980 and CYC065 (i.e., a mTOR/PI3K/CDK inhibitors) in in vitro and in vivo assays. This proposal encompasses the first integrated analysis of genomic differences in USC developed by AA when compared to C women as well as the validation of the currently identified differentially expressed genes harboring key driver mutations as novel targets for USC therapy in minority. Relevance Definition and functional validation of key driver mutations and downstream signaling pathways differentially active in AA women harboring USC may be used to guide novel, highly effective targeted therapies against these highly aggressive tumors and, therefore, may have immediate clinical relevance on minority health.