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: 7791370
• 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/7791370
• 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; 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年轻散发性结直肠癌（CRC）患者中发生的肿瘤的生物学特性。结直肠癌（CRC）是美国和欧洲最常见的致命癌症之一。 CRC 的研究主要集中在老年患者（50 岁以上）或具有家族倾向的年轻患者（50 岁以下）。家族性癌症综合征的两种主要形式已得到充分研究，即。遗传性非息肉病性结直肠癌（HNPCC）主要是由于错配修复基因的种系失活引起的，而家族性腺瘤性息肉病（FAP）主要是由于腺瘤性息肉病大肠杆菌肿瘤抑制基因的种系失活引起的。然而，对年轻人中发生的散发性结直肠癌的研究仍然有限。最近的几份报告表明，与美国和欧洲相比，非洲和亚洲发展中国家（包括印度）年轻散发性结直肠癌患者的比例有所增加。这些患者几乎占 CRC 患者总数的 1/4，并且经常死于侵袭性转移性疾病。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的肿瘤主要位于结肠。因此，有一些迹象表明，年轻人中发生的肿瘤可能与老年人中发生的类似肿瘤不同。在本次拨款申请中，我们建议对印度年轻人中发生的散发性结直肠癌与老年人中发生的散发性结直肠癌进行全面比较。将采用多管齐下的策略，包括 1) 筛查腺瘤性结肠息肉病 (APC) 肿瘤抑制基因的突变，2) 通过研究 β-连环蛋白和 Wnt 靶基因的转录谱分析来确定 Wnt 信号传导的状态，3) 筛查微卫星不稳定性，4) 识别反复出现的 DNA 拷贝数变化，以及 5) 分析全基因组基因表达谱。因此，本研究不仅有望对年轻散发性结直肠癌的分子基础产生有价值的见解，而且还可以为控制肿瘤发生和进展的细胞途径提供输入。公共卫生相关性：结直肠癌 (CRC) 是美国最常见和致命的癌症之一。非遗传性的年轻结直肠癌患者往往命运多舛，而且人们对这种类型的癌症还没有很好的了解。在我们目前的研究中，我们期望定义此类肿瘤的详细行为，这有望有助于未来设计更有效的疗法。

项目成果

Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation.

Ca2 /激活 T 细胞核因子信号传导在缺乏典型 Wnt 激活的早发性直肠肿瘤中丰富。

• DOI: 10.1007/s00109-017-1607-4
• 发表时间: 2018
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: Kumar,Raju;Raman,Ratheesh;Kotapalli,Viswakalyan;Gowrishankar,Swarnalata;Pyne,Saumyadipta;Pollack,JonathanR;Bashyam,MuraliD
• 通讯作者: Bashyam,MuraliD