Identification of Biomarkers for Testicular Cancer

睾丸癌生物标志物的鉴定

• 批准号: 7387821
• 负责人: Mohammad Obaidul Hoque
• 金额: $ 8.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387821
• 关键词: Accounting; Affect; Age; Algorithms; Alleles; Allelic Imbalance; Allelotyping; Area; Biological Assay; Biological Markers; Biology; Cancer cell line; Caucasians; Caucasoid Race; Cause of Death; Chromosomal Loss; Couples; DNA; Development; Diagnosis; Epigenetic Process; Event; Frequencies; Gene Targeting; Genes; Genetic; Genetic Recombination; Genome; Genomics; Genotype; Germ Cells; Germ cell tumor; Human; Human Genome; Hybridization Array; Incidence; Lead; Light; Localized; Logic; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of testis; Malignant neoplasm of urinary bladder; Maps; Methylation; Monitor; Mutation; Mutation Analysis; Numbers; Oncogene Activation; Oncogenes; Pattern; Play; Polymerase Chain Reaction; Population; Rate; Reporting; Role; Sampling; Seminoma; Sensitivity and Specificity; Single Nucleotide Polymorphism; Solid Neoplasm; Staging; Testicular Germ Cell Tumor; Testicular Neoplasms; Therapeutic; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; Upper arm; Urine; age group; aged; base; cancer type; epigenomics; insight; male; novel; novel diagnostics; promoter; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The incidence of testicular germ cell tumors (TGCT) has doubled in the past 40 years. An annual increase of 3-6% is reported for Caucasian populations. Testicular cancer is the most common malignancy affecting males aged 14-40 and accounting for up to 60% of all malignancies diagnosed at this age. Despite a high cure rate, they represent the most frequent cause of death from solid tumors in this age group. In addition to oncogene activation, the inactivation of tumor suppressor genes (TSGs) has been shown to play an important role in tumorigenesis. According to the revised Knudson's two-hit hypothesis, full inactivation of a tumor suppressor gene (TSGs) often involves two genetic or epigenetic events: 1) the loss or recombination of large chromosomal DNA regions containing one parental allele and a localized mutational event inactivating the second allele 2) localized mutation in one allele and methylation in another allele 3) LOH in one allele and methylation in another allele 4) biallelic methylation. We have recently discovered several cancer specific methylated genes by a robust approach that couples probabilistic search algorithms with the pharmacologic unmasking strategy for unbiased and precise global localization of tumor-specific methylated genes. We also validated a highthroughput assay for more than 50 genes (QMSP, quantitative methylation specific PCR) for robust analysis of several types of cancer with high sensitivity and specificity. In parallel, we have pioneered the use of single nucleotide polymorphism (SNP) arrays for analyzing cancer loss-of-heterozygosity (LOH) and performed a proof of principal study using SNP based arrays for the diagnosis of bladder cancer in urine sediment. We now propose the following aims: 1. To analyze patterns of chromosomal loss in testicular cancers from different stages using single nucleotide polymorphism (SNP) array hybridization of over 10,000 markers. 2. To discovery of testicular cancer specific methylated genes by a robust approach that couples probabilistic search algorithms in the entire human genome with an established pharmacologic unmasking strategy in cancer cell lines. 3. To compare the genomic and epigenomic patterns in different stages of testicular cancer. After carrying our first 2 specific aims, we will identify the gene or genes in a critical area of genetic and epigenetic alterations involved in testicular cancer. In addition, identification of these area and comparison of genetic and epigenetic alterations will shed important light on the biology of testicular cancer progression. Functional studies may provide insights into the first steps of germ cell immortilization and subsequent progression in cancer. Ultimately, SNP markers and methylation markers may lead to new diagnostic, monitoring and therapeutic approaches in testicular cancer. In addition this comprehensive analysis will lead us to understand the biology of testicular cancer development.

描述（由申请人提供）： 过去 40 年来，睾丸生殖细胞肿瘤 (TGCT) 的发病率翻了一番。据报道，白种人人口每年增加 3-6%。睾丸癌是影响 14-40 岁男性的最常见恶性肿瘤，占该年龄段诊断出的所有恶性肿瘤的 60%。尽管治愈率很高，但它们是该年龄段实体瘤最常见的死亡原因。除了癌基因激活之外，肿瘤抑制基因（TSG）的失活已被证明在肿瘤发生中发挥着重要作用。根据修订后的克努森双击假设，肿瘤抑制基因（TSG）的完全失活通常涉及两个遗传或表观遗传事件：1）包含一个亲本等位基因的大染色体DNA区域的丢失或重组以及使第二个等位基因失活的局部突变事件2）一个等位基因的局部突变和另一个等位基因的甲基化3）一个等位基因的LOH和 另一个等位基因的甲基化 4) 双等位基因甲基化。我们最近通过一种稳健的方法发现了几种癌症特异性甲基化基因，该方法将概率搜索算法与药理学揭示策略相结合，以实现肿瘤特异性甲基化基因的无偏见和精确的全局定位。我们还验证了针对 50 多个基因的高通量检测（QMSP，定量甲基化特异性 PCR），可对多种类型的癌症进行高灵敏度和特异性的稳健分析。与此同时，我们率先使用单核苷酸多态性 (SNP) 芯片来分析癌症杂合性缺失 (LOH)，并使用基于 SNP 的芯片诊断尿沉渣中的膀胱癌进行了主要研究证明。我们现在提出以下目标： 1. 使用超过 10,000 个标记的单核苷酸多态性 (SNP) 阵列杂交来分析不同阶段睾丸癌的染色体丢失模式。 2. 通过一种稳健的方法发现睾丸癌特异性甲基化基因，该方法将整个人类基因组中的概率搜索算法与癌细胞系中既定的药理学揭示策略相结合。 3. 比较睾丸癌不同阶段的基因组和表观基因组模式。在实现前两个具体目标后，我们将鉴定睾丸癌涉及的遗传和表观遗传改变关键区域的一个或多个基因。此外，这些区域的识别以及遗传和表观遗传改变的比较将为睾丸癌进展的生物学提供重要的线索。功能研究可以深入了解生殖细胞永生化的第一步以及癌症的后续进展。最终，SNP 标记和甲基化标记可能会带来睾丸癌新的诊断、监测和治疗方法。此外，这种全面的分析将引导我们了解睾丸癌发展的生物学。