Molecular Characterization of Sporadic Colorectal Cancer in the Young from India

印度年轻人散发性结直肠癌的分子特征

• 批准号: 7587366
• 负责人: JONATHAN R POLLACK
• 金额: $ 3.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587366
• 关键词: Accounting; Adenomatous Polyposis Coli; Africa; Applications Grants; Asia; Asians; Award; Behavior; Cancer Etiology; Cancer Patient; Cancer cell line; Cessation of life; Cholangiocarcinoma; Colon; Colorectal Cancer; Country; DNA Fingerprinting; DNA amplification; DNA copy number; Data; Data Analyses; Developed Countries; Developing Countries; Development; Diagnostic; Disease; Elderly; Europe; Future; Gene Amplification; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Government; Head; Hereditary Malignant Neoplasm; Hereditary Nonpolyposis Colorectal Neoplasms; India; Inherited; International; International Union Against Cancer; Joints; Laboratories; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Microsatellite Instability; Mismatch Repair Gene Inactivation; Molecular; Molecular Profiling; Mutation; Pancreas; Pathogenesis; Pathway interactions; Patients; Pattern; Predisposition; Protocols documentation; Publishing; Rectum; Recurrence; Reporting; Research Personnel; Research Project Grants; Role; Sampling; Screening procedure; Signal Transduction; Standardization; Stress; Syndrome; Technology Transfer; Transcript; Tumor Biology; Tumor Suppressor Genes; Visit; WNT Signaling Pathway; Work; Xenograft procedure; anticancer research; base; beta catenin; cancer type; comparative; comparative genomic hybridization; design; experience; genome-wide; insight; molecular oncology; novel; older patient; pancreatic neoplasm; parent grant; public health relevance; transcriptomics; tumor; tumor initiation

DESCRIPTION (provided by applicant): The main aim of the proposed work is to understand the biology of tumors occurring in young sporadic colorectal cancer (CRC) patients. Colorectal cancer (CRC) is one of the most common lethal cancers in USA and Europe. Studies on CRCs have mainly focused on either older patients (above 50 years) or younger patients (below 50 years) with a familial predisposition. Two major forms of familial cancer syndromes have been well studied viz. the Hereditary Non-polyposis Colorectal Cancer (HNPCC) caused mainly due to germline inactivation of mismatch repair genes and the Familial Adenomatous Polyposis (FAP) caused mainly due to the germline inactivation of the Adenomatous Polyposis Coli tumor suppressor gene. Studies on sporadic CRCs occurring in the young have however been limited. Several recent reports have indicated an increase in the proportion of young sporadic CRC patients in developing countries in Africa and Asia, including India, as compared to USA and Europe. These patients account for almost 1/4th of the total CRC patients and often succumb to aggressive metastatic disease. Moreover, the tumor in these patients is usually localized to the rectum, as against similar young patients from the USA and Europe, in which case the tumor is predominantly localized to the colon. There are therefore several indications that suggest that the tumors occurring in the young may be distinct from similar tumors occurring in the elderly. In the present grant application, we propose a comprehensive comparative characterization of sporadic CRCs occurring in the young with those occurring in the elderly, from India. A multi-pronged strategy would be used including 1) screening for mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene, 2) determination of status of Wnt signaling through studies on beta-catenin and transcript profiling of Wnt target genes, 3) screening for microsatellite instability, 4) identification of recurrent DNA copy number alterations and 5) analyses of genome-wide gene expression profiles. The present study therefore is not only expected to yield valuable insights into the molecular basis for young sporadic CRC but may also provide inputs into cellular pathways governing tumor initiation and progression in general. Public Health Relevance: Colorectal cancer (CRC) is one of the most common and lethal cancers in the USA. Non-hereditary young CRC patients often are ill fated, and this type of cancer is not understood well. In our present study, we expect to define the detailed behavior of this class of tumors, which is expected to aid in designing more efficient therapies in the future.

描述(由申请人提供)：拟议工作的主要目的是了解发生在年轻散发性结直肠癌(CRC)患者中的肿瘤生物学。结直肠癌(CRC)是美国和欧洲最常见的致命性癌症之一。关于CRCs的研究主要集中在有家族易感性的老年患者(50岁以上)或较年轻患者(50岁以下)。家族性癌症综合征的两种主要形式已经得到了很好的研究。遗传性非息肉病性结直肠癌(HNPCC)主要由错配修复基因种系失活引起，家族性腺瘤性息肉病(FAP)主要由腺瘤性息肉病结肠肿瘤抑制基因种系失活引起。然而，对发生在年轻人中的零星癌的研究一直很有限。最近的几份报告表明，与美国和欧洲相比，非洲和亚洲(包括印度)发展中国家的年轻散发性结直肠癌患者比例有所增加。这些患者几乎占全部结直肠癌患者的四分之一，并经常死于侵袭性转移疾病。此外，这些患者的肿瘤通常局限于直肠，而来自美国和欧洲的类似年轻患者，在这种情况下，肿瘤主要局限于结肠。因此，有几个迹象表明，发生在年轻人的肿瘤可能与发生在老年人的类似肿瘤不同。在目前的赠款申请中，我们建议对发生在年轻人中的零星CRC与发生在印度老年人中的CRC进行全面比较。将采用多管齐下的策略，包括1)筛查腺瘤性息肉病结肠(APC)抑癌基因的突变，2)通过研究β-连环素和Wnt靶基因的转录谱来确定Wnt信号的状态，3)筛选微卫星不稳定性，4)识别重复的DNA拷贝数改变，5)全基因组基因表达谱分析。因此，目前的研究不仅有望为年轻的散发性结直肠癌的分子基础提供有价值的见解，而且还可能为控制肿瘤发生和发展的细胞通路提供输入。公共卫生相关性：结直肠癌(CRC)是美国最常见和最致命的癌症之一。年轻的非遗传性结直肠癌患者往往命运不佳，这种类型的癌症并没有得到很好的了解。在我们目前的研究中，我们希望定义这类肿瘤的详细行为，这有望有助于未来设计更有效的治疗方法。