Tumor suppressor gene at 6q in adenoid cystic carcinoma

描述（申请人提供）：腺样囊性癌（ACC）是唾液腺中最常见的恶性肿瘤之一，但对这种疾病的分子机制知之甚少。先前和初步研究已经确定6号染色体长臂（6q）是ACC中经常缺失的区域。常见的缺失事件是其他癌症中已知肿瘤抑制基因的标记，本项目的目的是验证6q上存在一种新的肿瘤抑制基因的假设，该基因与ACC肿瘤发生有关。具体目标是1)提供6q上常见ACC缺失区域的更明确的遗传图谱，以缩小必须筛选的候选基因数量，2)测定肿瘤抑制基因的遗传特征的候选基因，3)测定肿瘤抑制基因的功能特征的候选基因。来源于腺样囊性癌的细胞系ACC3已被发现具有6q缺失，为了支持这些目的，该细胞系的缺失事件将得到更好的表征。将进行染色体转移实验，以确定ACC3是否可以作为一个模型系统来测试6q位点上的遗传物质对功能性肿瘤的抑制作用。实现这些目标和实现这些目标的可用资源包括现有的原发性ACC肿瘤样本收集，建立的ACC肿瘤登记处，唾液腺肿瘤组织微阵列和一组AGO和正常唾液腺组织的寡核苷酸微阵列基因表达数据。

DESCRIPTION (provided by applicant): Adenoid cystic carcinoma (ACC)is among the most common malignancies to arise in salivary glands, but little is known of the molecular mechanisms responsible for this disease. Prior and preliminary studies have identified the long arm of chromosome 6 (6q) as an area frequently deleted in ACC. Common deletion events are markers of known tumor suppressor genes in other cancers and the goal of this project is to test the hypothesis that a novel tumor suppressor gene exists on 6q which is responsible for ACC tumorigenesis. The Specific Aims are to 1) provide a more definitive genetic map of the common ACC deletion area on 6q in order to narrow the number of candidate genes that will have to be screened, 2) assay candidate genes for genetic characteristics of tumor suppressor genes and 3) assay candidate genes for functional characteristics of tumor suppressor genes. The cell line ACC3, derived from an adenoid cystic carcinoma, has been found to have a 6q deletion, and in support of these Aims, the deletion event in this cell line will be better characterized. Chromosomal transfer experiments will be performed to determine if ACC3 can serve as a model system to test for functional tumor suppression by genetic material on the 6q locus. Resources available to achieve these goals and carry out these Aims include an existing collection of primary ACC tumor samples, an established ACC tumor registry, a salivary gland tumor tissue microarray and oligonucleotide microarray gene expression data on a set of AGO and normal salivary gland tissue. There is no effective therapy for ACC, which is surgically non-resectable. Since there is an incomplete understanding of the molecular pathogenesis of ACC, there is little basis on which to rationally design and/or test new therapies. This application will address this deficiency. Since chromosome 6q deletions are common in other malignancies (breast cancer, ovarian cancer, melanoma) this knowledge may be generalizable to a larger population. Since AGO appears to have a smaller number of genetic changes than these other malignancies, it may serve as a simpler system to identify the 6q tumor suppressor gene.