Tumor suppressor gene at 6q in adenoid cystic carcinoma

描述(申请人提供)：腺样囊性癌(ACC)是发生在唾液腺的最常见的恶性肿瘤之一，但对导致这种疾病的分子机制知之甚少。先前和初步的研究已经发现，6号染色体的长臂(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的肿瘤抑制基因的标志，本项目的目的是验证6q上存在新的肿瘤抑制基因的假设，该基因与ACC的肿瘤发生有关。其具体目的是：1)提供6q上共同的ACC缺失区的更明确的遗传图谱，以减少需要筛选的候选基因的数量；2)检测抑癌基因的遗传特征；3)检测抑癌基因的功能特征。来源于腺样囊性癌的ACC3细胞系已被发现存在6q缺失，为了支持这些目的，该细胞系中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是否可以作为模型系统，测试6q基因座上的遗传物质对肿瘤的功能性抑制。可用于实现这些目标和实现这些目标的资源包括现有的原发ACC肿瘤样本收集、已建立的ACC肿瘤登记、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。 对于不能手术切除的ACC，目前还没有有效的治疗方法。由于对ACC分子发病机制的认识尚不完全，因此尚无合理设计和/或测试新疗法的依据。这个应用程序将解决这一缺陷。由于染色体6q缺失在其他恶性肿瘤(乳腺癌、卵巢癌、黑色素瘤)中很常见，这一知识可能可以推广到更大的人群中。由于AGR的基因改变似乎比这些其他恶性肿瘤要少，因此它可能是一种更简单的鉴定6q抑癌基因的系统。

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.