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假状态作为化学疗法反应和非洲结果的生物标志物 美国乳腺癌患者 抽象的 非裔美国人（AA）妇女被诊断出患有更高级和侵略性的乳腺癌，并有 即使控制已知的预后因素，也比白人/白人妇女较低的生存率，治疗 差异和社会经济地位。遗传和/或生物学因素被认为在 不同的生存率；但是，迄今为止很少有人发现潜在的生物标志物来解释AA乳房 癌症的生存差异及其机制知之甚少。我们的初步数据表明 大约40％ 白人/非AA女性的3％比肿瘤的固有亚型无关。虽然 DHFRP1-患者最初对新辅助治疗（NA）疗法反应良好，他们的复发时间较短 与NA处理的AA或白人患者的生存更糟 表明DHFRP1可能在对细胞毒性化学疗法，化学疗法和 AA妇女的癌症结果。源自DHFRP1-的永生淋巴母细胞系（LCLS） 饥饿后，患者不当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/或蛋白质调节中起功能。这里的工作 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（UNC）（侧重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）评估NA反应和临床结果（是时候到了 AA患者相对于DHFRP1状态的AA患者的复发性，特定于疾病的生存率）。体外研究还将检查 患者来源的LCL和AA乳腺癌细胞系，以表征遗传和分子作用 DHFRP1在化学敏感性和抗性中。我们提出了一种由DHFRP1状态介导的新型机制 过度的DHFR蛋白水平导致过度的细胞微环境，使得易感性 这些癌细胞具有高水平的基因组不稳定性，从而导致细胞毒性化学疗法抗性。结果 这些研究完成后获得的，预计将为替代个性化奠定基础 这些高危AA乳腺癌患者的治疗策略。