CANCER AND INFLAMMATION GENETICS

癌症和炎症遗传学

• 批准号: 8763440
• 负责人: MICHAEL DEAN
• 金额: $ 74.98万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763440
• 关键词: Accounting; Acute Lymphocytic Leukemia; Address; Adrenal Gland Neoplasms; Affect; African American; Age; Alleles; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Binding; Biological Assay; Birth; Bladder; CHEK2 gene; Cancer Hospital; Cancer Patient; Capital; Cells; Central America; Central American; Cervical; Characteristics; Child; Childhood Acute Lymphocytic Leukemia; Childhood Solid Neoplasm; China; Cities; Classification; Clear Cell; Clinical Data; Code; Collaborations; Country; DNA; Data; Databases; Diagnosis; Disease; Early Diagnosis; Elements; Epidemiology; Ethnic Origin; Europe; Exons; Family; Fathers; Female; Frequencies; Gene Expression; Gene Family; Gene Fusion; Genes; Genetic; Genome; Guatemala; Guatemalan; Handedness; High Prevalence; Hispanics; Hospitals; Incidence; Indigenous; Inflammation; Kidney; Kidney Neoplasms; Latin America; Loss of Heterozygosity; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Medical center; Metastatic Lesion; Methylation; Mexican Americans; Mexico; Minor; Minority; Molecular Analysis; Molecular Genetics; Mutate; Mutation; Mutation Spectra; Neoplasm Metastasis; Occupations; Oncogenic; PTEN gene; Patients; Population; Prevention; Promoter Regions; Prostate; Prostatic Diseases; Prostatic Neoplasms; Proteins; Protocols documentation; Public Health; Puerto Rico; RB1 gene; Reading; Renal carcinoma; Research; Retinoblastoma; Risk; Role; Sampling; Scanning; Sequence Analysis; Severities; Site; Solutions; Stage at Diagnosis; TP53 gene; Technology; Tissue Sample; United States; Universities; Validation; Variant; Woman; breast cancer family; cohort; early onset; exome; exome sequencing; follow-up; fusion gene; genetic analysis; genome sequencing; health disparity; high throughput technology; instrument; malignant breast neoplasm; mortality; olfactory receptor; oncology; programs; promoter; rural area; sample collection; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; urologic

Molecular Analysis of Breast Cancer in Minority Women Breast cancer remains the most common malignancy in females in the United States and is a major public health problem. Although progress has been made in prevention, early detection, and therapy, 37,500 women die of this malignancy annually. Although incidence of breast cancer is lower in minority women, significant health disparities exist for mortality, late diagnosis and triple negative disease. Analysis of breast cancer families resulted in the identification of two major loci, BRCA1 and BRCA2. These genes and several minor high-penetrant loci (PTEN, CHEK2, TP53) together account for 45-60% of disease in multiplex families. Therefore, there remain additional genes conferring risk for breast cancer. By establishing cohorts of minority women with breast cancer we hope to address some of these issues. We have begun collecting African American samples from Howard University and Hispanic samples from Puerto Rico. In addition we initiated a nationwide cohort of Hispanic breast cancer and have initiated recruitment. A collaboration with the Instituto Cancerologia and Hospital San Juan de Dios in Guatemala City has also been established and a protocol submitted to collect samples and data. 2. Prostate Cancer: Validation of Exome Sequencing and Application We applied Roche/454 exome sequencing technology to the sequencing of normal DNA and DNA from five different metastatic lesions in a single prostate cancer patient. More than 3 million reads were obtained on each of the normal and metastatic tumors resulting in greater than 25-fold coverage. Prediction of variants was carried out in each sample, and more than 500 variants that were present in three or more of the metastatic lesions were identified. We identified mutations in the TET2 gene, a gene previously known to be mutated solely in hematopoetic cancers. Analysis of the promoter region has identified the start site of the gene and major promoter elements. In addition we have performed binding partner analysis and identified new protein interactors. A collaboration with BGI in China will allow analysis of tumors from that region, and a collaboration with the Urological Oncology Branch, NCI, Walter Reed Medical Center and the Center for Prostate Disease Research (CPDR)will provide access to validation samples. 3. Kidney Tumor Exome and Transcriptome Sequencing To apply the technologies of high-throughput sequencing to renal cancer, we have used Illumina Solexa instrument for both transcriptome and exome sequencing. The Illumina exome approach uses an Agilent solution capture technology. DNA from two sporadic clear cell tumors were exome captured and sequenced to an average depth of 75-fold. From the sequence analysis, we identified a list of 101 genes with a newly described variant affecting the coding region, after eliminating genes from certain large, variable gene families, such as olfactory receptors. We further refined this list by analyzing the following characteristics: predicted severity of the mutation using Polyphen, SIFT, and other programs; presence of the same gene mutated in three out of five or more of the five genomes analyzed; presence of a mutation in that gene in the COSMIC database of cancer-related mutations; involvement of the gene in interactions with cancer-related proteins; and presence of loss of heterozygosity in the gene region in the tumors sequenced. From this combined analysis, we selected 16 genes as top priority for follow-up analysis. We have followed up on mutations of the PBRM1 gene and shown the gene to be mutated in approximately 40% of kidney tumors. We have undertaken expression analysis of these same tumors to understand the role of mutations in PBRM1 and VHL in expression in renal cancer. 4. Retinoblastoma in Latin America-Epidemiology and Genetic Analysis Retinoblastoma is one of the most common pediatric solid tumors in Mexico and Central America, accounting for up to 10% of all diagnosed cases, as opposed to 23% of all cases in the United States and Europe. Incidence calculations of retinoblastoma in Mexico have shown that the incidence varies within regions of the country and is highest in the Chiapas region bordering Guatemala. To further understand the factors involved in the higher prevalence, we performed an analysis of 246 consecutive cases treated over 8 years at the Unidad Nacional de Oncologia Pediatrica (UNOP), the sole pediatric cancer hospital in Guatemala. Data on age at diagnosis, birth region, laterality, ethnicity, and fathers occupation were captured, and this cohort was compared to a cohort of all cases with acute lymphocytic leukemia and as controls, children examined and found to be cancer-free. From this data we calculated the incidence of retinoblastoma to be 8.1 cases/million children under the age of 14 in the Guatemala City region. This incidence is elevated twofold over the incidence in the United States and Europe, and is similar in indigenous and admixed populations in the capital region. The elevated incidence is not due to an increase in familial cases, suggesting an environmental contributor. Analysis of retinoblastoma incidence in indigenous and admixed populations demonstrates a lower incidence in indigenous children in rural areas farther from the capitol. This disparity is even more pronounced in acute lymphocytic leukemia. Unilateral retinoblastoma accounted for 72% of cases. The average age of diagnosis and stage at diagnosis are advanced, resulting in reduced survival. To understand the spectrum of mutations in Guatemalan retinoblastoma cases, we mutation scanned and sequenced all 27 exons of the RB1 gene in 14 retinoblastoma tumors. Five different germline oncogenic mutations were detected in patients. In addition we developed a sensitive assay for methylation of the RB1 promoter and validated this assay on tissue samples. 5. Acute lymphocytic leukemia (ALL) is the most common childhood cancer. Our collaborators at St. Judes Hospital have identified the ARID5B gene locus as a major locus associated with pediatric ALL, especially the beta-hyperdiploid form. The risk alleles for ARID5B show significant differences in frequency in world populations and populations in Mexico and Guatemala have the highest frequencies described to date. Sample collection is in progress to study this further.

少数族裔女性乳腺癌的乳腺癌分子分析仍然是美国女性中最常见的恶性肿瘤，这是一个主要的公共卫生问题。尽管在预防，早期检测和治疗方面取得了进展，但每年有37,500名妇女死于这种恶性肿瘤。尽管少数族裔妇女的乳腺癌发病率较低，但死亡率，晚期诊断和三重阴性疾病存在重大健康差异。乳腺癌家族的分析导致了两个主要基因座BRCA1和BRCA2的鉴定。这些基因和几个次要的高渗透基因座（PTEN，CHEK2，TP53）占多重家族中疾病的45-60％。因此，还有其他基因赋予乳腺癌风险。通过建立乳腺癌的少数族裔妇女，我们希望解决其中一些问题。我们已经开始从霍华德大学收集非裔美国人样本，并从波多黎各收集了西班牙裔样本。此外，我们启动了全国性的西班牙乳腺癌队列，并开始招募。还建立了与危地马拉城的San Juan de Dios的合作，并已建立了一项协议，以收集样品和数据。 2。前列腺癌：外显子测序和应用的验证我们将Roche/454外显子组测序技术应用于单个前列腺癌患者中五个不同转移性病变的正常DNA和DNA的测序。每种正常和转移性肿瘤的读数都超过300万，导致覆盖率超过25倍。在每个样品中进行了变体的预测，并确定了三个或更多的转移性病变中存在的500多个变体。我们鉴定了TET2基因中的突变，TET2基因是一种以前已知仅在造血癌中突变的基因。对启动子区域的分析已经确定了基因和主要启动子元件的起始位点。此外，我们进行了结合伴侣分析并确定了新的蛋白质相互作用。与中国BGI的合作将允许对该地区的肿瘤进行分析，并与泌尿外科肿瘤科，NCI，Walter Reed医疗中心和前列腺疾病研究中心（CPDR）合作将提供验证样本。 3。肾脏肿瘤外显子组和转录组测序将高通量测序的技术应用于肾脏癌，我们使用Illumina Solexa仪器进行了转录组和外显子组测序。 Illumina Exome方法使用Agilent解决方案捕获技术。从两个零星的透明细胞肿瘤中的DNA被捕获，并测序为平均深度为75倍。从序列分析中，我们确定了101个基因的列表，其新描述的变体影响了编码区域，在消除了某些大型可变基因家族（例如嗅觉受体）的基因之后。我们通过分析以下特征进一步完善了这一列表：使用多芯子，SIFT和其他程序预测突变的严重程度；在分析的五个基因组中的五个或更多基因中，同一基因的存在被突变。该基因中存在突变在癌症相关突变的宇宙数据库中；该基因参与与癌症相关蛋白的相互作用；在测序的肿瘤中基因区域中杂合性丧失的存在。通过此组合分析，我们选择了16个基因作为后续分析的首要任务。我们已经跟踪了PBRM1基因的突变，并显示该基因在大约40％的肾脏肿瘤中被突变。我们已经对这些相同肿瘤进行了表达分析，以了解突变在PBRM1和VHL在肾脏癌中表达中的作用。 4。拉丁美洲 - 日常学和遗传分析的视网膜细胞瘤是墨西哥和中美洲最常见的儿科实体瘤之一，占所有被诊断病例的10％，而美国和欧洲的所有病例的23％。墨西哥视网膜母细胞瘤的发生率计算表明，该国地区的发病率有所不同，在与危地马拉接壤的恰帕斯地区最高。为了进一步了解较高的患病率的因素，我们对在危地马​​拉唯一的儿科医院的Unidad Nacional de Oncologia Pediatrica（UNOP）进行了8年的连续病例进行了分析。捕获了有关诊断，出生区域，侧向，种族和父亲职业的年龄的数据，并将该队列与所有患有急性淋巴细胞性白血病的病例的队列进行了比较，并且作为对照组，检查并被检查并发现没有癌症。从这些数据中，我们计算出危地马拉市地区14岁以下的视网膜母细胞瘤的发生率为8.1病例/百万儿童。在美国和欧洲的发病率上，这种发病率升高了，在首都地区的土著和混合人口中相似。发病率升高并不是由于家族病例的增加，表明环境贡献者。分析土著和混合种群中的视网膜细胞瘤发病率表明，距离国会大厦更远的农村地区的土著儿童的发病率较低。在急性淋巴细胞性白血病中，这种差异更为明显。单侧视网膜母细胞瘤占病例的72％。诊断和诊断时的平均诊断年龄是提高的，导致存活率降低。为了了解危地马拉视网膜细胞瘤病例中突变的频谱，我们在14个视网膜细胞瘤肿瘤中扫描并测序了所有27个RB1基因的外显子。在患者中检测到五种不同的种系致癌突变。此外，我们开发了一种对RB1启动子甲基化的敏感测定法，并在组织样品上验证了该测定法。 5。急性淋巴细胞性白血病（全部）是最常见的儿童癌症。我们在圣朱尼医院的合作者将ARID5B基因座确定为与儿科全部相关的主要基因座，尤其是β-二倍体形式。 ARID5B的风险等位基因在墨西哥和危地马拉的世界人群中显示出频率的显着差异，其迄今为止描述的频率最高。正在进行采集以进一步研究样本。