Molecular Characterization of Sporadic Colorectal Cancer in the Young from India

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。结直肠癌（CRC）是美国和欧洲最常见的致死性癌症之一。CRC的研究主要集中在有家族倾向的老年患者（50岁以上）或年轻患者（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，即主要由于错配修复基因的种系失活而引起的遗传性非息肉病性结直肠癌（HNPCC）和主要由于腺瘤性息肉病性结肠癌肿瘤抑制基因的种系失活而引起的家族性腺瘤性息肉病（FAP）。然而，对年轻人中发生的散发性CRCs的研究有限。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CRC患者的比例有所增加。这些患者几乎占总CRC患者的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不同于发生在老年人的类似肿瘤。在目前的拨款申请中，我们提出了一个全面的比较表征的散发性CRC发生在年轻人与老年人，从印度。将使用多管齐下的策略，包括1）筛选腺瘤性结肠息肉病（APC）肿瘤抑制基因中的突变，2）通过对Wnt靶基因的β-连环蛋白和转录谱的研究来确定Wnt信号传导的状态，3）筛选微卫星不稳定性，4）鉴定复发性DNA拷贝数改变和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CRC的分子基础产生有价值的见解，而且还可能为控制肿瘤发生和进展的细胞途径提供一般的输入。结直肠癌（CRC）是美国最常见和致命的癌症之一。非遗传性年轻CRC患者往往命运多舛，这种类型的癌症还不太清楚。在我们目前的研究中，我们希望定义这类肿瘤的详细行为，这有望有助于在未来设计更有效的治疗方法。

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.