CLONING OF THE 6Q27 TUMOR SUPPRESSOR GENE

染色体6q27的缺失与多种疾病密切相关 常见的肿瘤类型包括非霍奇金淋巴瘤(NHL；&GT；20%)、卵巢 癌症(&gt；70%)和乳腺癌(约50%)。损失 杂合性(LOH)、辐射杂交作图和克隆研究 确定了所有非霍奇金淋巴瘤病例常见的6q27内最小的丢失区域 在该区域内，包含最小区域的60kb次区域 在乳腺癌和卵巢癌中的损失。这些联系表明， 6q27可能含有肿瘤抑制基因(Dob1；在卵巢、乳腺中缺失 癌症和淋巴瘤)在多种癌症类型中发生改变。这样做的目的是 该项目是为了鉴定Dobl基因并阐明其作用 肿瘤发生的改变。将致力于实现以下具体目标： 1)通过基因定位的突变分析鉴定Dobl基因 乳腺癌中60kb最小缺失区的研究 携带杂合缺失或野生型6q27区域。2.筛选 卵巢癌、非霍奇金淋巴瘤等肿瘤的Dobl基因突变 确定6q27缺失是否与相同的抑制基因有关 在不同的肿瘤类型中。3.结构和图案的表征 通过确定Dobl基因产物的结构对其表达的影响 与已知蛋白质的组织和同源性及其亚细胞定位 及其在发育、组织增殖和发育过程中的表达模式 差异化。4.人血清白蛋白生物学功能的表征 Dobl基因，包括对其抑癌活性的分析 体外转基因细胞系及其对小鼠生殖系的破坏作用 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.