Zhang L, Yu J, Willson J K, Markowitz S D, Kinzler K W, Vogelstein B
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Cancer Res. 2001 May 1;61(9):3801-5.
Mismatch repair-deficient cancers are characterized by widespread insertions and deletions in microsatellite sequences, including those comprised of mononucleotide repeats. Such alterations have been observed in relatively short mononucleotide tracts in several genes and often are interpreted to indicate that the affected genes normally act as tumor suppressors. To aid in the interpretation of such changes, we have systematically assessed their frequency within transcribed regions of the genome that are unlikely to play a tumorigenic role. The advent of the complete human genomic sequences of chromosome 22 allowed us to select 29 genes for this analysis, spaced at approximately 1-Mb intervals. Each of the selected genes had an (A)(8) or a (G)(8) tract deep within intronic sequences that was not included in the processed transcript. Surprisingly, we found that there was substantial variation in the prevalence of mutations among these tracts. Some tracts were altered in < 5% of the mismatch repair-deficient cancers studied, whereas other tracts were altered in nearly half of the cancers. In particular, (G)(8) tracts were considerably more prone to mutation than (A)(8) tracts, and the sequences or chromatin structures surrounding the mononucleotide tracts seemed to affect their mutability significantly.
错配修复缺陷型癌症的特征是微卫星序列中存在广泛的插入和缺失，包括那些由单核苷酸重复组成的序列。在几个基因的相对较短的单核苷酸片段中已观察到此类改变，并且通常被解释为表明受影响的基因通常作为肿瘤抑制因子发挥作用。为了有助于解释此类变化，我们系统地评估了它们在基因组转录区域内的频率，这些区域不太可能发挥致瘤作用。22号染色体完整人类基因组序列的出现使我们能够选择29个基因进行此分析，这些基因以大约1兆碱基的间隔排列。每个选定的基因在内含子序列深处都有一个（A）（8）或一个（G）（8）片段，该片段不包含在加工后的转录本中。令人惊讶的是，我们发现这些片段中突变的发生率存在很大差异。在研究的错配修复缺陷型癌症中，有些片段的改变发生率小于5%，而其他片段在近一半的癌症中发生了改变。特别是，（G）（8）片段比（A）（8）片段更容易发生突变，并且单核苷酸片段周围的序列或染色质结构似乎对其可变性有显著影响。
