Prognostic value of AR mutation in primary African American prostate cancer

描述（由申请人提供）：非裔美国人（AA）男性前列腺癌（PCa）的发病率和死亡率高于白人美国人（CAs）。AA级前列腺癌患者肿瘤体积较大，肿瘤分期较晚，Gleason分级较高。前列腺癌的发生和肿瘤的进展与雄激素受体（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CAs中，AR突变在局部肿瘤中不常见（<1%），但在晚期、转移性或激素难治性疾病中发生的频率更高。在AAs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。我们在我们实验室建立的一株来自局限性PCa的AA患者的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例根治性前列腺切除术样本（57例AA和34例CAs），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患者中未发现突变。这些数据使我们假设原发性非裔美国人前列腺癌的AR突变比预期的更频繁，可能有助于疾病的侵袭性或作为预后因素。我们的具体目标是：目的1：确定原发性非裔美国人前列腺癌中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石蜡包埋组织切片激光捕获细胞中提取的基因组dna进行测序，以确定400例AA患者原发未治疗PCa的体细胞AR突变的发生率，并将该突变频率与100例同等CA患者的突变频率进行比较。目的2：确定AR突变对非裔美国人PCa异质性的贡献。前列腺癌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测AR突变的AA型PCa的AR和微血管密度。目的3：确定AR突变在原发性非裔美国人PCa中的预后意义。我们将确定AR突变单独或联合AR密度或微血管密度与临床或组织病理学变量的预后意义，包括年龄、PSA、Gleason评分、病理分期、生化复发和家族史，重点是Gleason总和或模式作为中心预后标志物。意义：本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前列腺癌在AAs和CAs中侵袭性的潜在种族差异。

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.