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

• 批准号: 8416144
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 15.37万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416144
• 关键词: Prognostic; value; AR; mutation; primary

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 highly to the expression and activity of the androgen receptor (AR). Mutations, genomic amplification, and polymorphisms in the CAG/GGC repeat 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. In addition, in a set of 41 radical prostatectomy samples (25 AAs and 16 CAs), we identified 4 AR mutations, 3 somatic and 1 germline in AA patients. These data led us to hypothesize that AR mutations in primary African-American PCa may be more frequent than expected and may contribute to disease aggressiveness or serve as a prognostic factor. We propose the following Specific Aims: 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 to determine the prevalence of somatic AR mutations in 250 AA patients with primary untreated PCa. 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 and PSA polymorphic sites in relation to prognostic clinical or histopathological variables including family history, age, PSA, 5 year PSA-free survival, primary Gleason pattern, Gleason sum, and TNM stage. Significance: The results of this exploratory (R21) project will provide both the prevalence and prognostic value of AR mutations and may help us to understand better and address more effectively the racial disparity of the aggressiveness of PCa in AAs when compared to Caucasians. 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男性也表现出更大的肿瘤体积、更晚期的肿瘤分期和更高的Gleason分级。前列腺癌的发生、发展与雄激素受体（AR）的表达和活性密切相关。CAG/GGC重复序列中的突变、基因组扩增和多态性也可增加AR表达和/或活性。在CA中，AR突变在局部肿瘤中很少发生（<1%），但在晚期、转移性或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。我们在本实验室建立的一个前列腺癌细胞系中发现了AR的基因组扩增和体细胞突变。此外，在一组41个根治性直肠癌切除术样本（25个AA和16个CA）中，我们在AA患者中鉴定出4个AR突变，3个体细胞突变和1个生殖细胞突变。这些数据使我们假设，AR突变在原发性非洲裔美国人PCa可能比预期的更频繁，可能有助于疾病的侵袭性或作为一个预后因素。我们提出以下具体目标：目标1：确定原发性非洲裔美国人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250例患有原发性未经治疗的PCa的AA患者中体细胞AR突变的患病率。目的2：确定AR突变对非裔美国人PCa异质性的贡献。PCa的临床和组织病理学异质性是治疗干预的主要挑战。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和微血管密度在AA PCa与突变的AR。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突变单独或与AR和PSA多态性位点联合与预后临床或组织病理学变量（包括家族史、年龄、PSA、5年无PSA生存率、原发性Gleason模式、Gleason总和和TNM分期）相关的预后意义。重要性：这项探索性（R21）项目的结果将提供AR突变的患病率和预后价值，并可能帮助我们更好地了解和更有效地解决与高加索人相比，AAs中PCa侵袭性的种族差异。 公共卫生相关性：非裔美国人（AA）男性前列腺癌（PCa）的发病率、死亡率和侵袭性均高于白人。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。我们发现在未经治疗的局部AA PCa中雄激素受体突变的频率很高，这可能具有预后意义，这将为我们提供一种更有效的治疗方法。

项目成果

ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models.

• DOI: 10.1002/ijc.28919
• 发表时间: 2014-12-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Parray A;Siddique HR;Kuriger JK;Mishra SK;Rhim JS;Nelson HH;Aburatani H;Konety BR;Koochekpour S;Saleem M
• 通讯作者: Saleem M