Frameshift mutations in the MBD4/MED1 gene in primary gastric cancer with high-frequency microsatellite instability

Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation

“…Furthermore, these findings support the notion that the observed mutations in the short mononucleotide repeat tract in the coding region of MBD4 of microsatellite unstable colorectal tumors are secondary to a mutator phenotype that is caused by MMR-deficiency or other repair deficiencies. Similar short repeat tract mutations in microsatellite unstable colorectal cancers are frequently found in the coding regions of a number of other genes that are important for tumor formation, including TGF-␤RII, IGF-IIR, and BAX, and the MMR genes MSH3 and MSH6 (14,24). If Mbd4 inactivation causes a mutator phenotype in cancer cells, it could potentially impact tumorigenesis.…”

“…A substantial number of these tumors were either HNPCC tumors that carried MLH1 mutations or sporadic tumors that had lost MSH2 or MLH1 expression as assessed by immunohistochemical analysis. In addition, MBD4 mutations were also frequently observed in other microsatellite unstable cancers such as gastric, endometrial, and pancreatic carcinomas (11,14). Sequence analysis of MBD4 in several of these tumors revealed that the vast majority of mutations occurred within a stretch of A (10) in the MBD4 coding region and were predicted to result in a truncated protein product that lacked the Cterminal catalytic domain.…”

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

“…In humans, a naturally occurring frameshift mutation of a polynucleotide tract in MBD4 has been found in microsatellite unstable (MSI) colon and other cancers (Bader et al, 1999;Riccio et al, 1999;Menoyo et al, 2001;Yamada et al, 2002) that leads to a premature stop in translation of the mRNA. The mutation occurs in 20 -43% of cases (mixed tissue samples), whereas microdissected samples (enriched for tumour cells) of 89% sporadic MSI colon tumours had truncated MBD4 mutations in at least one focus tested (Bader et al, 2000).…”

Is Base Excision Repair a Tumor Suppressor Mechanism?

“…37,38 Tumors resulting from alteration of mismatch repair genes and with high levels of microsatellite instability (MSI-H) synthesize a truncated MBD4 protein due to mutation of these repeats, as shown in Table 1. [37][38][39][40][41] In one study in which microdissected tumor tissue was analyzed, 17/19 (89%) of MSI-H colon carcinomas exhibited mutations within the MBD4 polyA (10) tract. 41 In contrast, only 1/22 (4.5%) of MSI-H gastric carcinomas harbored a mutation within the polyA tracts.…”

“…Four different variants of the MBD4 gene predicted to result in amino acid alterations of the protein were identified in gastric carcinomas. 39 Functional characterization of these variants has not been performed.…”