CLONING OF THE 6Q27 TUMOR SUPPRESSOR GENE

染色体6 q27的缺失与各种高频率相关。 常见的肿瘤类型包括非霍奇金淋巴瘤（NHL;> 20%）、卵巢癌（NHL;>20%）、淋巴瘤（NHL）、淋巴瘤（NHL）和淋巴瘤（NHL）。 癌（>70%）和乳腺癌（约50%）。损失 杂合性（洛合性缺失）、辐射杂交作图和克隆研究 在6 q27内发现了所有NHL病例共同的最小丢失区域 在此区域内，有一个60 kb的亚区，其中包含最小区域 乳腺癌和卵巢癌的死亡率。这些联系表明 6 q27可能含有一个肿瘤抑制基因（DOBL;在卵巢癌、乳腺癌和乳腺癌中缺失 癌和淋巴瘤）在多种癌症类型中改变。这个目标 该项目旨在鉴定DOBL基因，并阐明其作用。 肿瘤发生的改变。将努力实现以下具体目标： 1)用基因定位突变分析法鉴定DOBL基因 在乳腺癌病例中，在60 kb最小缺失区域内 携带杂合缺失或野生型6 q27区域。2.筛选 卵巢癌、NHL和其他肿瘤的DOBL突变， 确定是否相同的抑制基因参与6 q27缺失 在不同的肿瘤类型。3.结构和图案的表征 通过确定DOBL基因产物的结构， 组织和同源性已知的蛋白质，其亚细胞定位 及其在发育、组织增殖和 分化4.的生物学功能的表征 DOBL基因，包括其肿瘤抑制活性的分析， 体外转染的细胞系，及其在小鼠生殖系中的破坏 以确定其在体内组织发育和肿瘤发生中的作用。

Deletions of chromosome 6q27 are associated at high frequency with various common tumor types including non-Hodgkin lymphoma (NHL;>20%), ovarian carcinoma (>70%), and breast carcinoma (approximately 50%). Loss of heterozygosity (LOH), radiation-hybrid mapping and cloning studies have identified a minimal region of loss within 6q27 common to all NHL cases and, within this region, a 60kb subregion containing the minimal regions of loss in breast and ovarian carcinoma. These associations suggest that 6q27 may contain a tumor suppressor gene (DOBL; deleted in ovarian, breast carcinoma and lymphoma) altered in multiple cancer types. The goal of this project is to identify the DOBL gene and to elucidate the role of its alterations in tumorigenesis. The following specific aims will be pursued: 1) Identification of the DOBL gene by mutation analysis of genes mapping within the 60 kb minimal deletion region in breast carcinoma cases carrying heterozygous deletions or wild-type 6q27 regions. 2. Screening ovarian carcinoma, NHL and other tumors for DOBL mutations in order to determine whether the same suppressor gene is involved in 6q27 deletions in different tumor types. 3. Characterization of the structure and pattern of expression of the DOBL gene product by determining it structural organization and homology to known proteins, its subcellular localization and its pattern of expression during development, tissue proliferation and differentiation. 4. Characterization of the biological function of the DOBL gene, including the analysis of its tumor suppressor activity in transfected cell lines in vitro, and its disruption in the mouse germ-line to determine its role on tissue-development and tumorigenesis in vivo.