NOVEL MUTATOR PHENOTYPES IMPORTANT IN HUMAN COLON CANCER

本申请的目的是 明确分子机制和在人类结肠中的作用 三种新定义的遗传学上不同的结肠癌的发生 癌症"突变体"表型。申请人已检测到这些突变体 通过证明这些癌症具有10 - 100倍的 自发性HPRT基因突变率升高。 这些表型中的两种（包括六种细胞系）是新的， 不是由先前描述的DNA错配修复缺陷引起的 基因.这些发现补充了早期对突变机制的研究， 结肠癌，申请人和合作者已经证明， (1)遗传性非息肉病性结肠癌（HNPCC）综合征是由于 DNA错配修复途径缺陷成员的遗传 (MMR（2）具有MMR基因缺陷的肿瘤通常表现为 DNA微卫星的不稳定性（RER肿瘤）;（3）RER癌症也 发生在许多散发性癌症中，在这种情况下，MMR基因是 出乎意料的野生型。因此，申请人提出， 表型癌症是由不涉及任何 已知的MMR基因申请人的研究还证明了第二部小说 在非RER结肠中诱导序列不稳定性的增变子机制 癌的申请人的工作还表明， RER和非RER突变型肿瘤的不稳定性是全局性的， 表达基因的超突变性，而不是只影响 通常是非编码微卫星。申请人提出6项 具体目的：（1）描述DNA序列的特异性 靶向和自发突变产生的序列谱 （2）三种增变因子表型中的每一种;（3）确定 解释新的增变子表型的互补基团，和 将诱导这些表型的缺陷定位到单个染色体上; (3)为了阐明对特定环境类别的敏感性， 三种突变表型中每一种的诱变剂;（4）确定 新型非RER突变体在非RER结肠癌中的相对频率 表型;（5）确定转染的野生型DNA是否修复 基因将纠正突变表型，并将抑制任何其他 转移到突变癌中时转化表型的方面 缺乏野生型基因的细胞系;和（6）确定基因系是否 结肠癌突变基因的缺陷可以通过增加 病人淋巴细胞的突变率

DESCRIPTION: (Applicant's Abstract) The goal of this application is to define the molecular mechanisms and the role in human colon carcinogenesis of three newly defined and genetically distinct colon cancer "mutator" phenotypes. The applicant has detected these mutator type colon cancers by demonstrating that these cancers have 10-100 fold elevations in their rates of generating spontaneous hprt gene mutations. Two of these phenotypes (comprising six cell lines) are novel, and do not result from defects in previously described DNA mismatch-repair genes. These findings add to earlier studies of mutator mechanisms in colon cancer which the applicant and collaborators have demonstrated that (1) the Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome is due to inheritance of defective members of the DNA mismatch repair pathway (MMR genes); (2) tumors with MMR gene defects typically display instability of DNA microsatellites (RER tumors); (3) RER cancers also occur among many sporadic cancers, in which case MMR genes are unexpectedly wild type. Thus the applicant proposes that novel RER phenotype cancers are generated by defects not involving any of the known MMR genes. The applicant's studies also demonstrate a second novel mutator mechanism which induces sequence instability in non-RER colon cancers. Work by the applicant also demonstrates that genomic instability in RER and non-RER mutator type tumors is global, inducing hypermutability in expressed genes, as opposed to affecting only generally non-coding microsatellites. The applicant proposes six specific aims: (1) to characterize the specificity of DNA sequences targeted and the sequence spectrum of the spontaneous mutations produced by each of the three mutator phenotypes; (2) to determine the number of complementation groups accounting for the novel mutator phenotypes, and to map the defects inducing these phenotypes to individual chromosomes; (3) to elucidate the susceptibility to specific classes of environmental mutagens of each of the three mutator phenotypes; (4) to determine the relative frequency in Non-RER colon cancer of the novel Non-RER mutator phenotype; (5) to determine whether a transfected wild type DNA repair gene will correct the mutator phenotype and will suppress any other aspect of the transformed phenotype upon transfer into mutator cancer cell lines lacking the wild type gene; and (6) to determine if gene line defects in colon cancer mutator genes can be detected by an increased mutation rate in the patient's lymphocytes.