Integrated genomic analysis of racial disparities in endometrial cancer

描述(申请人提供)：尽管非裔美国人(AA)女性的子宫内膜癌发病率低于白人(C)女性，但美国子宫内膜癌存活率存在显著的种族差异，黑人的存活率比白人低30%。社会人口因素本身不能解释这种差异，因为当对黑人和白人妇女的分析按分期和生物学侵袭性(即II型)子宫内膜肿瘤进行调整时，生存差异仍然存在。子宫浆液性乳头状癌(USC)是子宫内膜癌中侵袭性最强的组织亚型。这种变异型子宫内膜癌在AA妇女中的发生率是C妇女的三倍。根据我们最近发表的关于USC遗传格局的数据，表明遗传和生物因素可能是导致存活率种族差异的基础，并最终目标是开发新的、更特异和更有效的治疗方法来诊断和治疗在AA女性中如此常见的USC，我们提出以下建议：目标1：通过整个外显子组测序确定200个USC样本中的候选突变、杂合性丢失(LOH)模式和拷贝数变异(CNV)，并使用生物信息学策略对AA和C肿瘤之间的遗传差异进行系统的评估。目的2：评估再生障碍性贫血和慢性丙型肝炎患者分化干细胞中miRNAs和mRNA的表达差异，并对不同类型分化干细胞(即c-erbB2+和阴性，以及PIK3CA和CCNE1突变株与野生型)中影响疾病的通路进行下游分析。目的3：评估一组新的PIK3CA突变的生化特性，并利用原代USC细胞株和靶向药物包括曲妥珠单抗和T-DM1(即靶向c-erbB2、AZD8055、GDC-0980和CYC065)，验证c-erbB2/PIK3CA和CCNE1通路是USC治疗的新靶点。MTOR/PI3K/CDK抑制剂)的体内外实验。该提案包含了第一个综合分析 对再生障碍性贫血与非再生障碍性贫血患者之间的基因组差异进行了研究，并验证了目前发现的含有关键驱动基因突变的差异表达基因是治疗少数族裔的新靶点。对患有USC的再生障碍性贫血患者的关键驱动因素突变和下游信号通路的相关性定义和功能验证可能被用来指导针对这些高度侵袭性肿瘤的新型、高效的靶向治疗，因此，可能对少数族裔的健康具有直接的临床意义。

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.