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：不分种族，50岁以下是目前大肠癌的筛查推荐年龄 (CRC)疾病的基础上的假设，即普遍的CRC差异是相对由于差异， 获得高质量的筛查和诊断后治疗。然而，一些证据表明， 提示，在较年轻的年龄组中，AA的CRC发病率是白人的两倍，他们的分期- 调整后的CRC生存率低于白人。鉴于大多数CRC是由癌前病变引起的， 腺瘤性息肉（adenopolyps）演变为浸润性腺癌，这是合理的，某些 “修饰”基因表达可能是AA经历中观察到的较早的原因。 腺瘤样息肉开始和更快的腺瘤样息肉进展为腺癌。如果是这样，一 CRC差异持续存在的潜在因素可能是种族差异/或中性年龄指南， 筛选启动。关于年龄相关的AA-白人在CRC进展中的差异的研究 需要中期（管状、管状绒毛状和绒毛状息肉大小，以及发育异常组织学）。到 要建立这样证据，需要对修饰基因和组织来源进行遗传改变研究 代表了足够大的尸检人群中结直肠腺瘤的患病率和特征 具有完整的息肉清除和完整的结直肠息肉记录的样本量。 我们的研究将利用640例结直肠腺瘤/癌症病例和1280例对照组织样本， 在我们的实验室和南方分部合作人体组织内进行频率匹配的嵌套病例对照 网络在亚拉巴马大学收集通过以前的NIH资助的研究。样本量有 有足够的统计学把握度比较AA和白人对结直肠腺瘤癌前病变患病率的影响 以及不同年龄层的癌症相关特征。这些组织收藏量很大，注释也很好 通过显微解剖。我们的实验室最近证明，在有线粒体的进行性增加， 结直肠腺瘤和癌与其正常周围组织相比的基因表达 组织（已接受的论文Tumor Biology #TUBI-16- 00926 R1），表明某些mt基因的表达是 参与结直肠腺瘤性息肉向浸润性腺癌的恶性转化。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中的癌前结肠直肠肿瘤行为，反映在其高发病率和低发病率中。 这种疾病的生存率。为了验证这一假设，我们将确定在20例受试者中mt-genes改变的水平。 AA-White亚组之间的结直肠腺瘤性息肉。此外，我们将评估我们的结果相对于AA-白色 10岁年龄层内的差异及其相关特征（大小、组织学、解剖位置、发育异常 状态和腺癌），以及体重指数（BMI），使用单变量统计检验，多变量 回归和聚类分析。