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患者化疗反应和结果的生物标志物- 美国乳腺癌患者 摘要 非裔美国人(AA)女性被诊断出患有更晚期和更具侵袭性的乳腺癌，并患有 即使在控制了已知的预后因素、治疗后，存活率也低于白人/白人妇女 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，到目前为止，还没有发现能解释再障乳房的潜在生物标志物。 癌症存活率差异及其机制目前还知之甚少。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-)，而 3%以上的白人/非AA女性，DHFRP1基因状态与肿瘤固有亚型无关。虽然 DHFRP1-患者最初对新辅助治疗反应良好，他们表现出较短的复发时间 与NA治疗的再生障碍性贫血或携带DHFRP1假基因(DHFRP1+)的白人患者相比， 提示DHFRP1可能在细胞毒化疗、化疗耐药和 再生障碍性贫血妇女的癌症结局。来源于DHFRP1的永生化淋巴母细胞系(LCLS) 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/或蛋白调控中发挥作用。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分校(UNC)(专注于基因组不稳定和遗传基因的作用 乳腺癌风险和治疗反应的差异)来评估NA反应和临床结果(时间 与DHFRP1状态相关的AA患者中的复发、疾病特异性存活)。体外研究也将检查 患者来源的LCLS和AA乳腺癌细胞系特征的遗传和分子作用(S) DHFRP1对化疗药物的敏感性和耐药性。我们提出了一种新的机制，由DHFRP1状态通过 哪种过高的dhfr蛋白水平会导致高度诱变的细胞微环境，从而使 这些癌细胞对基因组高度不稳定，导致细胞毒化疗耐药。结果是 在完成这些研究后，有望为替代个性化奠定基础 针对这些高危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.