Sammalkorpi Heli, Alhopuro Pia, Lehtonen Rainer, Tuimala Jarno, Mecklin Jukka-Pekka, Järvinen Heikki J, Jiricny Josef, Karhu Auli, Aaltonen Lauri A
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.
Cancer Res. 2007 Jun 15;67(12):5691-8. doi: 10.1158/0008-5472.CAN-06-4314.
Microsatellite instability (MSI) is observed in approximately 12% of colorectal cancers. Genes containing a mononucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87% were observed in 8 to 10 bp tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repair-deficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.
在大约12%的结直肠癌中可观察到微卫星不稳定性（MSI）。在MSI肿瘤发生过程中，编码序列中含有单核苷酸微卫星的基因特别容易失活，并且已经开展了大量工作来鉴定这些肿瘤中具有高重复序列突变率的基因。人们对背景突变频率的关注要少得多，并且尚无研究聚焦于非转录区域。在此，我们研究了114个长度为6至10 bp、位于远离已知基因处的非转录基因间A/T和C/G重复序列，以检测MSI结直肠癌中的背景突变频率。观察到与序列长度有很强的相关性，在8至10 bp的序列中观察到高达87%的突变频率。随后，为了比较转录和非转录非编码重复序列中的背景突变率，我们筛选了9个随机选择的内含子C/G8重复序列。此外，还分析了7个推测的MSI靶基因的编码重复序列，以及9个先前发表的内含子A8和G8重复序列。内含子重复序列的突变频率似乎低于非转录基因间重复序列。我们的结果表明，错配修复缺陷细胞中的链滑动突变在短基因间重复序列中与许多推测的MSI靶基因中一样丰富。然而，在错配修复缺陷的情况下，转录序列中的链滑动突变似乎比基因间非转录序列中的更有效地得到修复。导致这些差异的机制尚不清楚，应作为进一步研究的课题。对于MSI靶基因的鉴定，转录序列中的重复序列似乎是编码区重复突变最合适的参考组。
