Hypermethylation of the DNA mismatch repair gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer.
BACKGROUND
It remains to be investigated whether the aberrant methylation of DNA repair genes plays a pathogenic role in BRAF mutation-promoted tumorigenesis of papillary thyroid cancer (PTC).


METHODS
In the current study, the promoter methylation status of 23 DNA repair genes in relation to clinicopathologic characteristics and BRAF mutation was examined in PTC tumors using methylation-specific polymerase chain reaction.


RESULTS
Among the 38 PTC tumors examined, 3 of 23 DNA repair genes were hypermethylated, including the hMLH1 gene in 8 of 38 samples (21%), the PCNA gene in 5 of 38 samples (13%), and the OGG1 gene in 2 of 38 samples (5%). Methylation of these genes was also found in some thyroid cancer cell lines. Methylation of the hMLH1 gene in particular was found to be associated with lymph node metastasis of PTC (5 of 8 samples [63%] in the methylation group vs 3 of 30 samples [10%] in the nonmethylation group; P = .0049). Methylation of the hMLH1 gene was also found to be associated with the T1799A BRAF mutation in PTC (6 of 19 samples (32%) in the BRAF mutation-positive group vs 2 of 19 samples (11%) in the BRAF mutation-negative group; P = .042).


CONCLUSIONS
The data from the current study suggest that, as shown previously in colon cancer, aberrant methylation of the hMLH1 gene may play a role in BRAF mutation-promoted thyroid tumorigenesis.
Guan
Haixia
H
Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Ji
Meiju
M
Hou
Peng
P
Liu
Zhi
Z
Wang
Cuifang
C
Shan
Zhongyan
Z
Teng
Weiping
W
Xing
Mingzhao
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D013936:Thymidine / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D000241:Adenosine; D013936:Thymidine