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）女性子宫内膜癌的发病率低于白人(C)女性，但在美国，子宫内膜癌的生存率存在显著的种族差异，黑人的生存率比白人低30%。单独的社会人口因素不能解释这种差异，因为当分析根据分期和生物侵袭性（即II型）子宫内膜肿瘤对黑人和白人妇女进行调整时，生存率仍然存在差异。子宫浆液乳头状癌（USC）是子宫内膜癌中最具侵袭性的组织学亚型。这种变异的子宫内膜癌在AA型女性中的发病率是C型女性的三倍。根据我们最近发表的关于USC遗传景观的数据，遗传和生物学因素可能是导致存活率种族差异的原因，我们的最终目标是为AA女性中常见的USC的诊断和治疗开发新的，更具体和更有效的治疗方法，我们提出以下建议：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、杂合性缺失（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评估，目的2：评估AA和C在USC中的mirna和mRNA表达差异，并对不同USC组（即C - erbb2 +与阴性，PIK3CA和CCNE1突变体与野生型）中影响疾病的途径进行下游分析，以及Aim 3：评估新型PIK3CA突变子集的生化特性，并在体外和体内试验中验证c-erbB2/PIK3CA和CCNE1途径作为USC治疗的新靶点，使用原代USC细胞系和靶向药物，包括曲珠单抗和T-DM1（即靶向c-erbB2的单克隆抗体），AZD8055， GDC-0980和CYC065（即mTOR/PI3K/CDK抑制剂）。这个建议包含了第一个综合分析

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.