Colorectal cancer disparities:Racial differences in colorectal adenopolyps and altered expression of Mitochondrial genes

结直肠癌差异：结直肠腺息肉的种族差异和线粒体基因表达的改变

• 批准号: 9280274
• 负责人: Felix O Aikhionbare
• 金额: $ 10.65万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280274
• 关键词: Adenocarcinoma; Adenomatous Polyps; Affect; African American; Age; Age-Years; Alabama; Anatomy; Architecture; Area; Autopsy; Behavior; Biology; Biopsy; Biopsy Specimen; Body mass index; Carcinoma; Caucasians; Clinical; Cluster Analysis; Colorectal; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Colorectal Polyp; Coupling; Data; Diagnostic; Disease; Documentation; Dysplasia; Early Diagnosis; Epithelium; Frequencies; Funding; Gene Expression; Gene Mutation; Genes; Genetic Polymorphism; Genome; Genomics; Gland; Goals; Guidelines; Histologic; Histology; Histopathology; Incidence; Individual; Laboratories; Large Intestine Carcinoma; Lesion; Link; Location; Malignant Neoplasms; Microdissection; Mitochondria; Mitochondrial DNA; Molecular Profiling; Morphology; Mutation; Normal tissue morphology; Outcome; Oxidative Stress; PTGS2 gene; Paper; Patients; Pattern; Persons; Play; Polyps; Population; Precancerous Polyp; Predisposition; Premalignant; Prevalence; Proteins; Quantitative Reverse Transcriptase PCR; RNA; Race; Recommendation; Regression Analysis; Research Design; Reverse Transcription; Risk Assessment; Role; Sample Size; Sampling; Source; Statistical Data Interpretation; Subgroup; Sulfhydryl Compounds; Surface; Survival Rate; Testing; Tissue Banks; Tissue Sample; Tissues; Transcript; Tubular formation; Tubulovillous Adenoma; Tumor Biology; Tumor stage; United States National Institutes of Health; Universities; Variant; Villous; Villous Adenoma; Work; adenoma; age difference; age group; age related; aged; base; biomarker identification; cancer health disparity; carcinogenesis; case control; caucasian American; clinically relevant; cohort; early experience; experience; genetic variant; human tissue; innovation; insertion/deletion mutation; insight; mitochondrial DNA mutation; novel; outcome forecast; overexpression; polyposis; predict clinical outcome; public health relevance; racial difference; racial disparity; repaired; screening; treatment strategy; tumor; tumor progression

Abstract: Regardless of race, 50 years of age is the current screening recommendations for colorectal cancer (CRC) disease based on an assumption that the prevailing CRC disparities are relatively due to differences in access to quality screening and the post diagnostic therapies. However, several lines of evidence have suggested that in younger age groups, AA have twice the CRC incidence rate as Whites, and their stage- adjusted CRC survival rates are lower than Whites. Given that most CRCs arise from precancerous of adenomatous polyps (adenopolyps) that evolve into invasive adenocarcinoma, it is plausible that certain “modifying” genes expression may potentially responsible for the observation in AA experience to earlier adenopolyps initiation and more rapid adenopolyps progression to adenocarcinoma. If such is the case, one potential factor in the persistent of CRC disparities may be the race-nonconforming/or neutral age guideline for screening initiation. Studies regarding age-related AA-White differences in CRC progression through the intermediate stages (polyp sizes of tubular, tubulovillous, and villous, and dysplastic histology) are needed. To establish such evidence, it requires genetic alteration study in a modifying gene(s) and a tissue source representing the colorectal adenopolyp prevalence and profile in the population from a large enough autopsy sample size with complete adenopolyps clearance and having complete colorectal adenopolyps documentation. Our study will leverage a unique of 640 colorectal adenopolyp/ cancer cases and 1280 control tissue samples in a frequency matched nested case-control within our lab and Southern Division Co-operative Human tissues Network at University of Alabama collected through previous NIH-funded studies. The sample size has sufficient statistical power to compare AA and Whites on precancerous of colorectal adenopolyps prevalence and cancer-relevant features with difference age strata. These tissue collections are large and well-annotated by micro-dissection. Our laboratory recently demonstrated that there were progressive increase of mitochondrial gene expressions in colorectal adenopolyps and carcinomas when compared to their normal surrounding tissues (accepted paper Tumor Biology #TUBI-16-00926R1), suggesting that certain mt-genes expression are involved in the malignancy of colorectal adenopolyps to invasive adenocarcinoma. Based on these data, the central hypothesis of this project is that over-expression of certain mt-genes play a role in the aggressiveness of precancerous colorectal tumor behavior within younger AA which are reflected in their high incidence and low survival rate of this disease. To test this hypothesis, we will determine the level of mt-genes alterations in colorectal adenopolyps between AA-White subgroups. Also, we will evaluate our results relative to AA-White differences within 10 year age strata and their related features (size, histology, anatomic location, dysplasia status, and adenocarcinoma), as well as body mass index (BMI) using univariate statistical tests, multiple regression and cluster analysis.

摘要：无论种族如何，50岁是目前结直肠癌筛查建议 （CRC）疾病基于这样的假设：普遍的 CRC 差异是相对由于差异造成的 获得高质量筛查和诊断后治疗。然而，多项证据表明 研究表明，在较年轻的年龄组中，AA 的 CRC 发病率是白人的两倍，而且他们的分期 调整后的结直肠癌存活率低于白人。鉴于大多数 CRC 源自癌前病变 腺瘤性息肉（腺息肉）演变为侵袭性腺癌，某些情况似乎是合理的 “修改”基因表达可能是 AA 经历中观察到更早现象的潜在原因 腺息肉的起始和更快的腺息肉进展为腺癌。如果是这种情况，一 CRC 差异持续存在的潜在因素可能是种族不符合/或中性年龄准则 筛查启动。关于 CRC 进展中与年龄相关的 AA-White 差异的研究 需要中间阶段（息肉大小为管状、管状绒毛状和绒毛状，以及发育不良的组织学）。到 建立这样的证据，需要对修饰基因和组织来源进行遗传改变研究 通过足够大的尸检来代表人群中结直肠腺息肉的患病率和概况 具有完整的腺息肉清除率和完整的结直肠腺息肉文档的样本量。 我们的研究将利用 640 个结直肠腺息肉/癌症病例和 1280 个对照组织样本中的独特数据 我们实验室和南部部门合作人体组织内的频率匹配嵌套病例对照 阿拉巴马大学网络通过之前 NIH 资助的研究收集。样本大小有 有足够的统计能力来比较 AA 和白人对结直肠腺息肉癌前病变患病率的影响 以及不同年龄层的癌症相关特征。这些组织收藏量大且注释清楚 通过显微解剖。我们的实验室最近证明线粒体逐渐增加 与正常周围环境相比，结直肠腺息肉和癌中的基因表达 组织（已接受论文《肿瘤生物学》#TUBI-16-00926R1），表明某些 mt 基因表达 参与结直肠腺息肉向侵袭性腺癌的恶变。根据这些数据， 该项目的中心假设是某些 mt 基因的过度表达在 年轻 AA 中的癌前结直肠肿瘤行为反映在其高发病率和低发病率 这种疾病的生存率。为了检验这个假设，我们将确定 mt 基因改变的水平 AA-White 亚群之间的结直肠腺息肉。此外，我们将评估相对于 AA-White 的结果 10岁年龄层内的差异及其相关特征（大小、组织学、解剖位置、发育不良 状态和腺癌），以及使用单变量统计检验的体重指数（BMI）、多重 回归和聚类分析。