TGF-B RECEPTOR GENE MUTATIONS DETECTED IN HUMAN CANCER

这项提议的目标是阐明自然产生的人类 恶性肿瘤导致转化生长因子-β途径失活的新分子缺陷 对肿瘤的抑制。我们的小组最近进行的调查 合作者已经确定转化生长因子-β受体是一种新的成员 肿瘤抑制基因家族，并已表明转化生长因子-β受体 基因突变在某些结肠癌的发病机制中起重要作用。 转化生长因子-β抑制多种上皮细胞类型的生长 一例既能消除未转化细胞生长，又能诱导细胞凋亡的例子 结肠上皮细胞。相比之下，结肠和许多其他癌细胞 该细胞系对转化生长因子-β生长抑制具有抗性。我们最近的研究 已经证实在一组结肠癌中对转化生长因子-β耐药 由于II型成分的体细胞突变而失活 (RII)的转化生长因子-β受体复合体。此外，我们已经表明， 通过RII基因转移纠正这种结肠癌中的RII突变 细胞取消了细胞形成肿瘤的能力。转化生长因子-β受体 因此是一种新的肿瘤抑制因子，其失活直接导致 致癌的原因。转化生长因子-β受体由一个异二聚体组成。 I型(RI)和II型(RII)亚单位的复合体。在模型系统中， RI或RII的突变使受体复合体失活并使 转化生长因子-β抗性。这项提议的假设是，大多数 肿瘤通过RII组分突变逃避转化生长因子-β生长控制 转化生长因子-β受体，转化生长因子-β的RI型成分突变 β受体，或转化生长因子-β下游成分的突变 信号通路。 我们最初确定了RII突变主要发生在10个碱基内 存在于RII编码序列中的成对多腺苷重复序列(BAT-RII)和 我还发现这些突变只是那些结肠的特征 也证明了微卫星基因缺陷的癌症 不稳定(RER结肠癌)。RER表型具有以下特征 结肠癌、子宫内膜癌和胃癌高发于 遗传性非息肉病性结肠癌家族性癌 综合症。在许多近端癌症(右)中也存在RER 侧面)结肠、子宫内膜和胃出现在个体之间 在一般人群中不属于癌症家族。 最近，我们已经在一些RER结肠癌中发现了新的 (非BAT-RII)RII突变位点。最近，我们还 在非RER结肠癌中发现首例新病例 RII突变的位置，以及第一个可能携带 转化生长因子-β信号通路中RII后元件的突变。这个 这项提议的具体目标现在将决定：i)这些小说如何 突变功能不活跃的转化生长因子-β信号；ii)有多常见 转化生长因子-β抵抗在非RER结肠癌变中的作用 癌症；III)非RER结肠癌中转化生长因子-β耐药的频率 由RII突变、RI突变或POST中的缺陷所介导 转化生长因子-β信号通路的受体成分；iv) BAT-RII突变在某些特定类型的RER癌发生中的作用 非结肠组织(胃和子宫内膜)，以及非RER是否 胃癌和子宫内膜癌，如非RER结肠癌， 其他使转化生长因子-β信号失活的新突变。最后， 我们将确定对BAT-RII突变的诊断测试是否会 允许早期发现人的RER结肠癌。

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.