TGF-B RECEPTOR GENE MUTATIONS DETECTED IN HUMAN CANCER

在人类癌症中检测到 TGF-B 受体基因突变

• 批准号: 2733292
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 40.37万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733292
• 关键词: athymic mouse; biological signal transduction; carcinogenesis; clinical research; colon neoplasms; epithelium; gastrointestinal neoplasms; gene mutation; growth factor receptors; human subject; immunoprecipitation; monoclonal antibody; mutant; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic growth; nucleic acid repetitive sequence; pathologic process; phenotype; polymerase chain reaction; tissue /cell culture; transforming growth factors; tumor suppressor genes; uterus neoplasms; western blottings

The goal of this proposal is to elucidate among naturally occurring human malignancies novel molecular defects that inactivate the TGF-beta pathway of tumor suppression. Recent investigations by our group of collaborators have identified the TGF-beta receptor as a new member of the tumor suppressor gene family and have shown that TGF-beta receptor gene mutation is important in the pathogenesis of certain colon cancers. TGF-beta inhibits the growth of many epithelial cell types and for example both abolishes growth of and induces apoptosis in nontransformed colon epithelial cells. In contrast, colon and many other cancer cell lines are resistant to TGF-beta growth suppression. Our recent studies have demonstrated TGF-beta resistance in one group of colon cancers is due to the inactivation by somatic mutation of the type II component (RII) of the TGF-beta receptor complex. Moreover, we have shown that correcting, by RII gene transfer, the RII mutations in such colon cancer cells abolishes the cells capacity to form tumors. The TGF-beta receptor is thus a novel tumor suppressor whose inactivation directly contributes to carcinogenesis. The TGF-beta receptor is composed of a heterodimeric complex of type I (RI) and type II (RII) subunits. In model systems, mutation of either RI or RII inactivates the receptor complex and confers TGF-beta resistance. The hypothesis of this proposal is that most cancers escape TGF-beta growth control by mutation of the RII component of the TGF-beta receptor, mutation of the type RI component of the TGF- beta receptor, or mutation of downstream components of the TGF-beta signalling pathway. We initially identified RII mutations predominantly within a ten base pair polyadenine repeat (BAT-RII) present in the RII coding sequence and also identified these mutations as characteristic only of those colon cancers that also demonstrated the genetic defect of microsatellite instability (RER colon cancers). The RER phenotype is characteristic of colon, endometrial and gastric cancers that arise with high incidence in kindreds with the Hereditary Nonpolyposis Colon Cancer familial cancer syndrome. RER is also present in many cancers of the proximal (right sided) colon, the endometrium and the stomach arising among individuals in the general population who do not belong to cancer families. Recently, we have now identified in some RER colon cancers added novel (not BAT-RII) sites of RII mutation. Most recently, we have also identified among NonRER colon cancer the first case that bears a novel site of RII mutation, and an added case that is the first to likely bear a mutation in post-RII elements of the TGF-beta signalling pathway. The specific aims of this proposal will now determine: i) how these novel mutations functionally inactive TGF-beta signalling; ii) how commonly TGF-beta resistance contributes to carcinogenesis among NonRER colon cancers; iii) how often TGF-beta resistance in NonRER colon cancers is mediated by RII mutations, by RI mutations, or by defects in post receptor components of the TGF-beta signalling pathway; iv) the role of BAT-RII mutations in the genesis of RER cancers characteristic of certain noncolonic tissues (stomach and endometrium), as well as whether NonRER gastric and endometrial cancers, like NonRER colon cancers, bear additional novel mutations that inactivate TGF-beta signalling. Lastly, we will determine whether a diagnostic test for BAT-RII mutations will allow early detection in man of RER colon cancers.

这项提案的目的是阐明自然发生的人类 阻碍TGF-β途径的恶性肿瘤新分子缺陷 抑制肿瘤的方法。 我们小组最近的调查 合作者已经确定TGF-β受体作为一个新的成员， 肿瘤抑制基因家族，并显示TGF-β受体 基因突变在某些结肠癌的发病机制中是重要的。 TGF-β抑制许多上皮细胞类型的生长， 在一个实施例中，既消除了非转化细胞的生长，又诱导了细胞凋亡。 结肠上皮细胞。 相反，结肠癌和许多其他癌细胞 品系对TGF-β生长抑制具有抗性。 我们最近的研究 已经证明了一组结肠癌中的TGF-β抵抗， 由于II型组分的体细胞突变失活 (RII)转化生长因子β受体复合物。 此外，我们已经证明， 通过RII基因转移纠正这种结肠癌中的RII突变 细胞消除了细胞形成肿瘤的能力。 tgf-β受体 因此是一种新的肿瘤抑制因子，其失活直接有助于 到致癌作用。 TGF-β受体由异二聚体组成， I型（RI）和II型（RII）亚基的复合物。 在模型系统中， RI或RII的突变使受体复合物失活， TGF-β抵抗。 这一提议的假设是， 癌症通过RII组分突变逃避TGF-β生长控制 TGF-β受体的RI型组分突变， TGF-β受体或TGF-β下游成分突变 信号通路 我们最初发现RII突变主要在10个碱基内， 存在于RII编码序列中的成对聚腺嘌呤重复序列（BAT-RII），以及 我还发现这些突变仅是那些结肠癌的特征， 癌症也表现出微卫星的遗传缺陷， 不稳定（RER结肠癌）。 RER表型的特征是 结肠癌、子宫内膜癌和胃癌， 遗传性非息肉病性结肠癌家族性癌的发病机制 综合征 粗面内质网也存在于许多近端癌（右 侧）结肠，子宫内膜和胃之间产生的个人 不属于癌症家族的普通人群。 最近，我们发现在某些RER结肠癌中增加了新的 (not BAT-RII）RII突变位点。 最近，我们还 在非RER结肠癌中发现了第一例具有新的 RII突变位点，以及第一个可能携带 TGF-β信号通路的后RII元件中的突变。 的 这一建议的具体目标现在将决定：i）这些小说如何 功能上无活性的TGF-β信号传导突变; ii） TGF-β耐药导致非RER结肠癌的发生 iii）非RER结肠癌中TGF-β耐药的频率 由RII突变、RI突变或后基因缺陷介导， TGF-β信号通路的受体组分; iv） 在RER癌发生中的BAT-RII突变是某些 非结肠组织（胃和子宫内膜），以及非RER 胃癌和子宫内膜癌，如非RER结肠癌， 另外的新突变抑制TGF-β信号传导。 最后， 我们将确定BAT-RII突变的诊断测试是否 可以早期发现RER结肠癌。