The Role of Microsatellite Instability in Cancer

描述（由申请人提供）：虽然上皮源性癌症的完整病因尚不清楚，但已确定了几个相关的遗传和环境因素。作为肿瘤发生的标志物和促成因素受到越来越多关注的一类特定遗传事件涉及微卫星长度突变，表现为微卫星改变（MA）和微卫星不稳定性（MSI）（Forgacs et al.，2001; Woerner等人，2001年）。微卫星重复序列在哺乳动物基因组中是常见的，并且经常是多态的。我们已经开发并验证了用于预测微卫星的算法，微卫星最有可能发生频繁突变（Fondon等人，1998年）。体细胞微卫星长度突变通常在结肠癌、子宫内膜癌、乳腺癌和胃癌中观察到，并且已显示为一些肺癌的突出特征（吉拉德（Girard）等人，2001; Forgacs等人，2001; Wistuba等人，2000年）。MSI已被证明是DNA错配修复基因缺陷的表现，并且是DNA错配修复中一类缺陷的有用指标。我们假设体细胞和生殖细胞微卫星突变可能在某些癌症的发生和发展中起重要的病因作用，了解它们在上皮来源的癌症类型中的突变频率、复杂性和多样性，以及了解它们在不同正常遗传背景中的变化是至关重要的。我们已经检查了基因相关微卫星的基因组，并确定了超过10,000个基因的转录区域内的基因可能会经历扩展和/或收缩突变的位点。其中许多在编码区中，其中8%预测在改变时导致移码变体，并且一些在肿瘤抑制子中（Wren et al.，2001年）。在目标1中，我们将改进用于预测与癌症进展相关的微卫星突变事件的方法，扫描最近完成的人类基因组，以预测已知或怀疑在肿瘤发生中起作用的基因中的重复多态性，并选择这些基因座中的约150个用于来自肺癌、乳腺癌、卵巢癌和结肠直肠癌细胞系的一组DNA中的基因分型（目标2），包括许多具有匹配的B淋巴细胞DNA以及原发肿瘤和正常血液DNA的患者。我们还将（目标3）研究目标2中确定的这些突变对剪接的影响，将其与剪接异构体的定量全球调查结果相关联。

DESCRIPTION (provided by applicant): While the complete etiology of epithelial-derived cancers is not yet known, several correlative genetic and environmental factors have been identified. One specific class of genetic events receiving increasing attention as both a marker and a contributing factor of oncogenesis involves microsatellite length mutations, manifested as microsatellite alteration (MA) and microsatellite instability (MSI) (Forgacs et al., 2001; Woerner et al., 2001). Microsatellite repeats are common and often polymorphic in mammalian genomes. We have developed and verified algorithms for predicting microsatellites, which are most likely to be subject to frequent mutation (Fondon et al., 1998). Somatic microsatellite length mutations are commonly observed in colon, endometrial, breast, and stomach cancers, and have been shown to be a prominent feature of some lung cancers (Girard, et al., 2001; Forgacs, et al., 2001; Wistuba et al., 2000). MSI has been shown to be a manifestation of defects in DNA mismatch repair genes, and is a useful indicator of a class of defects in DNA mismatch repair. We hypothesize that both somatic and germline microsatellite mutation may play an important etiological role in the development and progression of some cancers, and it is critical to have knowledge of their mutational frequency, complexity, and diversity among types of epithelial-derived cancers, as well as an understanding of how they vary in different normal genetic backgrounds. We have inspected the genome for gene-associated microsatellites, and have identified over 10,000 loci within transcribed regions of genes that are likely to experience expansion and/or contraction mutations. Many of these are in coding regions, with 8% of these predicted to result in frame-shifting variants when altered and some are in tumor suppressors (Wren et al., 2001). In Aim 1 we will refine methods for predicting microsatellite mutation events associated with cancer progression, scan the recently completed human genome for predicted repeat polymorphisms in genes known or suspected to have a role in tumorigenesis, and select -150 of these loci for genotyping (Aim 2) in a panel of DNAs from lung, breast, ovarian and colorectal cancer cell lines, including many with matched B lymphocyte DNAs in addition to primary tumor and normal blood DNAs. We will also (Aim 3) investigate the effects of these mutations identified in Aim 2 on splicing by correlating them with the results of a quantitative global survey of splicing isoforms.