Prognostic value of AR mutation in primary African American prostate cancer

AR 突变在非裔美国人原发性前列腺癌中的预后价值

基本信息

批准号：
7989304
负责人：
SHAHRIAR KOOCHEKPOUR
金额：
$ 19.98万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989304
关键词：
Address African American Age American Androgen Receptor Androgens Benign Biochemical Cancer Patient Cancer-Predisposing Gene Caucasians Caucasoid Race Cell Line Cells Clinical DNA DNA Binding Domain Data Diagnostic Neoplasm Staging Disease Epidemiologist Event Exons Family history of Flow Cytometry Frequencies Gene Mutation Gene Targeting Genomics Germ-Line Mutation Gleason Grade for Prostate Cancer Heterogeneity Hormones Incidence Individual Knowledge Laboratories Lasers Lead Malignant - descriptor Malignant neoplasm of prostate Molecular Mutate Mutation Natural History Outcome PC3 cell line Paraffin Embedding Pathological Staging Pathologist Patients Pattern Prevalence Prognostic Factor Prognostic Marker Prostate Prostate-Specific Antigen Radical Prostatectomy Receptor Gene Recurrence Refractory Refractory Disease Reporting Sampling Somatic Mutation Specimen Staging Staining method Stains Testing Therapeutic Therapeutic Intervention Tissue Banking Tissue Banks Tissues Tumor Volume Tumor stage cancer site caucasian American density laser capture microdissection men mortality novel prognostic prostate carcinogenesis protein expression public health relevance receptor receptor density receptor expression receptor-mediated signaling tissue resource tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) incidence and mortality rate is higher in African American (AA) men than in Caucasian Americans (CAs). AA men with PCa also present with higher tumor volume, more advanced tumor stage, and higher Gleason grade. Prostate carcinogenesis and tumor progression are related strongly to the expression and activity of the androgen receptor (AR). Mutations and genomic amplification of AR also can increase AR expression and/or activity. In CAs, AR mutations are infrequent (<1%) in localized tumors, but occur at a higher frequency in advanced, metastatic, or hormone-refractory disease. In AAs, the prevalence of AR mutations and their prognostic significances in primary PCa are unknown. We discovered genomic amplification and somatic mutation of AR in a PCa cell line established by our laboratory from an AA patient with localized PCa. We analyzed a set of 91 radical prostatectomy samples (57 AAs and 34 CAs) in which we identified 8 AR mutations (7 somatic and 1 germline) in AA patients, but found no mutations in CA patients. These data led us to hypothesize that AR mutations in primary African Americans PCa is more frequent than expected and may contribute to disease aggressiveness or serve as a prognostic factor. Our Specific Aims are: Aim 1: Determine the prevalence of AR mutations in primary African Americans PCa. Exon-specific primers of the AR gene will be used to sequence genomic-DNA extracted from laser-captured cells of paraffin- embedded tissue sections of radical prostatectomy specimens in order to determine the prevalence of somatic AR mutations in 400 AA patients with primary untreated PCa, and compare this frequency of mutation with that observed in 100 equivalent CA patients. Aim 2: Determine the contribution of AR mutation to PCa heterogeneity in African Americans. Clinical and histopathological heterogeneity of PCa present a major challenge to therapeutic interventions. Differences in AR expression and microvascular density are considered as the two major contributors to PCa heterogeneity. We will use flow cytometry and immunohistochemical staining to examine AR and microvessel density in AA PCa with mutated AR. Aim 3: Define the prognostic significance of AR mutations in primary African American PCa. We will determine the prognostic significance of AR mutations alone or in combination with AR density or microvessel density in relation to clinical or histopathological variables including age, PSA, Gleason score, pathological stage, biochemical recurrence, and family history, with a focus on Gleason sum or pattern as a central prognostic marker. Significance: The results of this exploratory project will provide new knowledge about both the prevalence and prognostic value of AR mutations and may help us to understand better and address more effectively the potential racial disparity between PCa aggressiveness in AAs and CAs. PUBLIC HEALTH RELEVANCE: The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African-American (AA) men are higher than in Caucasians. To understand and address the racial disparity of the disease aggressiveness, reliable prognostic factors are needed. Our discovery of a high frequency of androgen receptor mutations in untreated localized AA PCa might have prognostic significance that would provide us a more effective therapeutic approach.

描述（由申请人提供）：非洲裔美国人 (AA) 男性的前列腺癌 (PCa) 发病率和死亡率高于白人美国人 (CA)。患有 PCa 的 AA 男性还表现出更大的肿瘤体积、更晚期的肿瘤分期和更高的格里森分级。前列腺癌发生和肿瘤进展与雄激素受体（AR）的表达和活性密切相关。 AR 的突变和基因组扩增也可以增加 AR 的表达和/或活性。在 CA 中，AR 突变在局部肿瘤中很少见 (<1%)，但在晚期、转移性或激素难治性疾病中发生频率较高。在 AA 中，AR 突变的患病率及其在原发性 PCa 中的预后意义尚不清楚。我们在我们实验室从患有局部 PCa 的 AA 患者中建立的 PCa 细胞系中发现了 AR 的基因组扩增和体细胞突变。我们分析了一组 91 个根治性前列腺切除术样本（57 个 AA 和 34 个 CA），其中我们在 AA 患者中发现了 8 个 AR 突变（7 个体细胞和 1 个种系），但在 CA 患者中没有发现突变。这些数据使我们推测，原发性非裔美国人 PCa 中的 AR 突变比预期更频繁，可能会导致疾病侵袭性或作为预后因素。我们的具体目标是：目标 1：确定原发性非裔美国人 PCa 中 AR 突变的患病率。 AR 基因的外显子特异性引物将用于对从根治性前列腺切除术标本的石蜡包埋组织切片的激光捕获细胞中提取的基因组 DNA 进行测序，以确定 400 名未经治疗的原发性 PCa AA 患者中体细胞 AR 突变的患病率，并将该突变频率与 100 名同等 CA 患者中观察到的突变频率进行比较。目标 2：确定 AR 突变对非裔美国人 PCa 异质性的影响。 PCa 的临床和组织病理学异质性对治疗干预提出了重大挑战。 AR 表达和微血管密度的差异被认为是 PCa 异质性的两个主要因素。我们将使用流式细胞术和免疫组织化学染色来检查具有突变 AR 的 AA PCa 中的 AR 和微血管密度。目标 3：确定 AR 突变在原发性非洲裔美国人 PCa 中的预后意义。我们将确定 AR 突变单独或与 AR 密度或微血管密度结合的预后意义，与临床或组织病理学变量相关，包括年龄、PSA、格里森评分、病理分期、生化复发和家族史，重点是格里森总和或模式作为中心预后标志。意义：这个探索性项目的结果将提供关于 AR 突变的患病率和预后价值的新知识，并可能帮助我们更好地理解和更有效地解决 AA 和 CA 中 PCa 侵袭性之间的潜在种族差异。公共卫生相关性：非洲裔美国 (AA) 男性前列腺癌 (PCa) 的发病率、死亡率和侵袭性高于白种人。为了了解和解决疾病侵袭性的种族差异，需要可靠的预后因素。我们在未经治疗的局部 AA PCa 中发现的雄激素受体突变频率较高的发现可能具有预后意义，这将为我们提供更有效的治疗方法。