DHFRP1 pseudogene status as a biomarker of chemotherapy response and outcomes in African-American breast cancer patients

DHFRP1 假基因状态作为非裔美国乳腺癌患者化疗反应和结果的生物标志物

• 批准号: 10017920
• 负责人: Jacquelyn J Bower
• 金额: $ 16.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017920
• 关键词: 3' Untranslated Regions; Adjuvant; Adjuvant Therapy; Affect; African American; Age; Biological; Biological Assay; Biological Factors; Biological Markers; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; CRISPR/Cas technology; Caucasians; Cell Line; Clinical; Clinical Research; Clinical Treatment; Collection; Comprehensive Cancer Center; Cytotoxic Chemotherapy; DNA; Data; Development; Diagnosis; Dihydrofolate Reductase; Disease; Exhibits; Generations; Genes; Genetic; Genetic Markers; Genetic Variation; Genomic Instability; Genotoxic Stress; Genotype; Goals; In Vitro; Individual; Letters; Leukocytes; Luciferases; Malignant Neoplasms; Mediating; Molecular; Neoadjuvant Therapy; North Carolina; Nucleotides; Outcome; Patients; Play; Prognostic Factor; Proteins; Pseudogenes; Publishing; Recurrence; Regulation; Relapse; Reporter; Reporting; Resistance; Role; Series; Socioeconomic Status; Starvation; Stress; Survival Rate; Testing; Time; Transcript; Transcriptional Regulation; Tumor Subtype; Universities; Western Blotting; Woman; Work; breast cancer survival; cancer cell; chemotherapy; clinically relevant; cytotoxic; diagnostic assay; follow-up; genotoxicity; high risk; hormone therapy; lymphoblastoid cell line; malignant breast neoplasm; novel; overexpression; personalized medicine; personalized strategies; personalized therapeutic; potential biomarker; response; survival outcome; treatment response; tumor

Title: DHFRP1 pseudogene status as a biomarker of chemotherapy response and outcomes in African- American breast cancer patients ABSTRACT African-American (AA) women are diagnosed with more advanced and aggressive breast cancers and have lower survival rates than Caucasian/white women even after controlling for known prognostic factors, treatment differences, and socioeconomic status. Genetic and/or biological factors are thought to play a critical role in disparate survival rates; however, to date few potential biomarkers have been identified to explain AA breast cancer survival disparities and their mechanisms are poorly understood. Our preliminary data suggests that approximately 40% of AA breast cancer patients lack the DHFRP1 pseudogene (DHFRP1-) compared to less than 3% of white/non-AA women, and DHFRP1 status was unrelated to tumor intrinsic subtype. Although DHFRP1- patients initially responded well to neoadjuvant (NA) therapy, they exhibited shorter time to recurrence and worse survival than NA-treated AA or white patients harboring the DHFRP1 pseudogene (DHFRP1+), suggesting that DHFRP1 may play a role in the response to cytotoxic chemotherapy, chemoresistance, and cancer outcomes among AA women. Immortalized lymphoblastoid cell lines (LCLs) derived from DHFRP1- patients inappropriately retained high levels of the dihydrofolate reductase (DHFR) protein upon starvation, suggesting that DHFRP1 may play a functional role in DHFR gene and/or protein regulation. The work herein proposes to expand upon these preliminary findings to determine the clinical relevance of DHFRP1(+/-) status by taking advantage of the unique Lineberger Comprehensive Cancer Center (LCCC) 9830 clinical study at the University of North Carolina at Chapel Hill (UNC) (which is focused on the role of genomic instability and genetic variation in breast cancer risk and therapeutic response) to assess NA response and clinical outcomes (time to recurrence, disease specific survival) in AA patients relative to DHFRP1 status. In vitro studies will also examine patient-derived LCLs and AA breast cancer cell lines to characterize the genetic and molecular role(s) of DHFRP1 in chemosensitivity and resistance. We propose a novel mechanism mediated by DHFRP1 status by which excessive DHFR protein levels results in a hyper-mutagenic cellular microenvironment that predisposes these cancer cells to high levels of genomic instability leading to cytotoxic chemotherapy resistance. The results obtained upon completion of these studies are expected to lay the groundwork for alternative personalized therapeutic strategies for these high-risk AA breast cancer patients.

标题：DHFRP1 假基因状态作为非洲化疗反应和结果的生物标志物 美国乳腺癌患者 抽象的 非裔美国 (AA) 女性被诊断出患有更晚期和更具侵袭性的乳腺癌，并且患有 即使在控制已知的预后因素、治疗后，存活率仍低于白人/白人女性 差异和社会经济地位。遗传和/或生物因素被认为在 不同的存活率；然而，迄今为止，很少有潜在的生物标志物被确定来解释 AA 乳房 人们对癌症生存差异及其机制知之甚少。我们的初步数据表明 大约 40% 的 AA 乳腺癌患者缺乏 DHFRP1 假基因 (DHFRP1-) 少于 3% 的白人/非 AA 女性，并且 DHFRP1 状态与肿瘤内在亚型无关。虽然 DHFRP1-患者最初对新辅助（NA）治疗反应良好，他们的复发时间较短 与 NA 治疗的 AA 或携带 DHFRP1 假基因 (DHFRP1+) 的白人患者相比，生存率更差， 表明 DHFRP1 可能在细胞毒性化疗、化疗耐药和 AA 女性的癌症结果。源自 DHFRP1- 的永生化类淋巴母细胞系 (LCL) 患者在饥饿时不恰当地保留高水平的二氢叶酸还原酶（DHFR）蛋白， 表明 DHFRP1 可能在 DHFR 基因和/或蛋白质调节中发挥功能作用。本文的工作 建议扩展这些初步发现以确定 DHFRP1(+/-) 状态的临床相关性 通过利用独特的 Lineberger 综合癌症中心 (LCCC) 9830 临床研究 北卡罗来纳大学教堂山分校 (UNC)（专注于基因组不稳定性和遗传的作用） 乳腺癌风险和治疗反应的变化）来评估 NA 反应和临床结果（治疗时间） AA 患者相对于 DHFRP1 状态的复发率、疾病特异性生存率。体外研究还将检查 源自患者的 LCL 和 AA 乳腺癌细胞系，用于表征其遗传和分子作用 DHFRP1 的化学敏感性和耐药性。我们提出了一种由 DHFRP1 状态介导的新机制 过量的 DHFR 蛋白水平会导致高诱变细胞微环境，从而诱发 这些癌细胞的基因组高度不稳定，导致细胞毒性化疗耐药。结果 完成这些研究后获得的结果预计将为替代性个性化奠定基础 这些高风险 AA 乳腺癌患者的治疗策略。