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

标题：DHFRP1假基因状态作为非洲人化疗反应和结局的生物标志物- 美国乳腺癌患者 摘要 非裔美国人（AA）女性被诊断患有更晚期和侵袭性乳腺癌， 即使在控制了已知的预后因素、治疗后，生存率也低于白人/白色女性 差异和社会经济地位。遗传和/或生物因素被认为在以下方面起关键作用： 不同的生存率;然而，迄今为止，很少有潜在的生物标志物已被确定为解释AA乳腺癌 癌症存活差异及其机制知之甚少。我们的初步数据显示， 大约40%的AA乳腺癌患者缺乏DHFRP1假基因（DHFRP1-），而 白色/非AA女性中DHFRP1的阳性率低于3%，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，他们表现出较短的复发时间 和比NA治疗的AA或携带DHFRP1假基因（DHFRP1+）的白色患者更差的存活率， 这表明DHFRP1可能在细胞毒性化疗、化疗耐药性和 AA女性的癌症结局。来源于DHFRP1的永生化淋巴母细胞样细胞系（LCL）- 患者在饥饿时不适当地保留了高水平的二氢叶酸还原酶（DHFR）蛋白， 提示DHFRP1可能在DHFR基因和/或蛋白调节中发挥功能性作用。本文中的工作 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， 位于查佩尔山的北卡罗来纳州大学（该大学专注于基因组不稳定性和遗传学的作用） 乳腺癌风险和治疗反应的变化），以评估NA反应和临床结局（至 复发，疾病特异性生存）。体外研究还将检查 患者来源的LCL和AA乳腺癌细胞系来表征的遗传和分子作用 DHFRP1在化疗敏感性和耐药性中的作用我们提出了一种新的机制介导的DHFRP1状态， 过量的DHFR蛋白质水平导致高度诱变的细胞微环境， 这些癌细胞基因组高度不稳定，导致细胞毒性化疗抗性。结果 这些研究完成后获得的预期奠定了基础，替代个性化 这些高危AA乳腺癌患者的治疗策略。

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.