Aberrant and Overexpression of DNA Methyltransferase in KRAS Mutant Pulmonary Adenocarcinomas
Weiqiang Zhao, Konstantin Shilo, Shujun Liu, Miguel A Villalona, Gregory A Otterson, Charles Hitchcock, Yan Tang. The Ohio State University Medical Center, Columbus, OH; University of Minnesota, Rochester, MN
Background: Correlation between KRAS mutations and pulmonary adenocarcinomas (PA) has been well documented. We have previously shown that majority of the KRAS G12/G13 mutations is transversion (G>T and G>C) in PA compared to colorectal adenocarcinomas (p= 0.011). The aim of this study was to evaluate for possible relationships between transverse mutations and expressions of enzymes associated with DNA methylation and oxidative stress in KRAS mutant PA.
Design: A total of 109 PA patients without EGFR TKD mutations (Exon19 and 21) were enrolled in this study. Genomic DNA was used for KRAS G12/G13 codon mutation testing by direct sequencing. A tissue microarray consisting of 62 PA samples including 26 PA with KRAS mutation was evaluated for the expression of DNMT1, DNMT3a, and NQO1 by immunohistochemistry. The correlations between markers expression and clinicopathologic variables were examined by Kruskal-Wallis ranks test and Spearman Rank Order test.
Results: Among 26 mutant KRAS gene, 84.6% were transverse mutation. Moreover, 21 of 22 transverse mutation are G>T (>95%). No correlation was present between patients' KRAS mutation status and age or sex. The presence of KRAS mutations, however, was associated with increased expression of DNMT1 (r=0.582, p<0.0001), NQO1 (r=0.436, p=0.0004), and DNMT3A (r=0.35, p=0.0053) in the tumor cells. Nuclear expression of DNMT1 was seen in 25 of tumors (25/62), and majority (77.3%) of them had KRAS mutation (p=0.0054).
Conclusions: In this study, we further confirmed that most KRAS mutations in PA were C>T transverse mutation. The association between KRAS mutation and upregulation of nuclear DNA methyltransferase (DNMT1, DNMT3a) expressions in the tumor cells suggest aberrant activation of DNMT might involve in the KRAS G12/G13 mutation in PA.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 300, Tuesday Morning