Alterations of the base excision repair gene MUTYH in sporadic colorectal cancer
Alterations of the base excision repair gene MUTYH in sporadic colorectal cancer
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DOI：
10.3892/or.2012.1836
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发表时间：
2012-08-01
期刊：
影响因子：
4.2
通讯作者：
Tomita, Naohiro
中科院分区：
文献类型：
--
作者：
Kuno, Takashi;Matsubara, Nagahide;Tomita, Naohiro
碱基切除修复基因MUTYH编码糖基化酶，其去除与8-氧代-7，8-二氢-2'-脱氧鸟苷（8-OHG）错配的腺嘌呤残基。已知MUTYH基因的双等位基因生殖系突变会导致多发性结直肠腺瘤，包括息肉病和癌症，主要是由于原癌基因或肿瘤抑制基因中的G：C-> T：A颠换。MUTYH单等位基因突变携带者患结直肠癌（CRC）的风险估计高于非携带者。为了研究MUTYH基因在散发性结直肠癌中的作用，我们检测了101例散发性结直肠癌中MUTYH基因的改变，包括体细胞突变和等位基因丢失，以及某些病例中的KRAS突变。3例癌细胞DNA中检测到MUTYH突变，而正常组织DNA样本中也发现突变，表明均为种系突变。在51例CRC病例中有10例（20.0%）发现MUTYH基因座的等位基因丢失，在101例样本中有33例（32.7%）发现KRAS突变。在KRAS中G：C-> T：A颠换率在有等位基因丢失的病例（10例中1例，10.0%）和没有等位基因丢失的病例（41例中9例，22.0%）之间没有显著差异。对MUTYH SNP rs3219489处的定量等位基因失衡的调查显示，C等位基因占优势（对应于His的次要类型）的CRC病例比G等位基因占优势（对应于Gln的主要类型）的CRC病例更容易检测到G：C-> T：A颠换。总之，散发性CRC中MUTYH的体细胞改变是罕见的，类似于其他DNA修复基因。然而，可能是本研究中未分析的未知区域突变和MUTYH启动子区域的表观遗传变化可能导致该疾病。
The base excision repair gene MUTYH encodes glycosylase which removes adenine residues mispaired with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHG). Biallelic germline mutations of the MUTYH gene are known to cause multiple colorectal adenomas including polyposis and cancer, mostly due to G:C -> T:A transversions in proto-oncogenes or tumor suppressor genes. The risk of colorectal cancer (CRC) in monoallelic mutation carriers of MUTYH is estimated to be higher in comparison with non-carriers. To investigate the possible role in sporadic CRC, we examined alterations of the MUTYH gene including somatic mutations and allelic loss in 101 cases of sporadic CRC, together with the KRAS mutation in some cases. MUTYH mutations in cancer DNA were detected in 3 cases, while mutations were also found in DNA samples from normal tissues, indicating that all were germline mutations. Allelic loss at the MUTYH locus was found in 10 of 51 (20.0%) CRC cases and KRAS mutations were found in 33 of the 101 (32.7%) samples. There was no significant difference in the rate of G:C -> T:A transversion in KRAS between cases with allelic loss (1 of 10, 10.0%) and without allelic loss (9 of 41, 22.0%). Investigation of quantitative allelic imbalance at SNP rs3219489 of MUTYH showed that CRC cases with C allele dominance (minor type corresponding to His) were more frequently detected with G:C -> T:A transversions than in those with G allele dominance (major type corresponding to Gln). In conclusion, somatic alterations of MUTYH in sporadic CRC were rare, similar to other DNA repair genes. However, it is possible that unknown mutations of regions not analyzed in this study and epigenetic changes of the promoter region of MUTYH may contribute to the disease.