Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis.
Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis.
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DOI：
10.18632/oncotarget.5740
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发表时间：
2015-12-15
期刊：
影响因子：
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通讯作者：
Bellacosa A
中科院分区：
文献类型：
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作者：
Tricarico R;Cortellino S;Riccio A;Jagmohan-Changur S;Van der Klift H;Wijnen J;Turner D;Ventura A;Rovella V;Percesepe A;Lucci-Cordisco E;Radice P;Bertario L;Pedroni M;Ponz de Leon M;Mancuso P;Devarajan K;Cai KQ;Klein-Szanto AJ;Neri G;Møller P;Viel A;Genuardi M;Fodde R;Bellacosa A
DNA糖基化酶基因MBD 4保护CpG位点的基因组稳定性，并且在错配修复（MMR）缺陷的结直肠肿瘤（CRC）中在编码poly-A轨道处频繁突变。小鼠中mbd 4双等位基因失活提供了关于其在肿瘤发生中的作用的相互矛盾的结果。因此，目前还不清楚MBD 4的改变是否只是继发于MMR缺陷而没有功能后果，或者可以促成增变基因表型。我们研究了一系列遗传性/家族性和散发性CRC病例中的MBD 4变异体。然而MBD 4移码仅在肿瘤中检测到，错义变体在正常和肿瘤DNA中均被发现。在具有双MBD 4/MMR和单MBD 4变体的CRC中，过渡突变频率增加，表明MBD 4缺陷可能独立于MMR缺陷而影响突变格局。Mbd 4缺陷小鼠与Mlh 1 −/−基因型结合时，存活率降低。总之，这些数据表明MBD 4失活可能有助于肿瘤发生，作为MMR缺陷型癌症表型的修饰剂。
The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1−/− genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype.