IDH1 and IDH2 Mutations Detected by Pyrosequencing in Cholangiocarcinoma
Jesse S Voss, Sarah E Kerr, Emily G Barr Fritcher, W Edward Highsmith, Jun Zhang, Lewis R Roberts, Gregory J Gores, Kevin C Halling, Benjamin R Kipp. Mayo Clinic, Rochester, MN
Background: Somatic mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in gliomas and can help stratify brain cancer patients into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aim of this study was to determine the frequency of IDH1 and IDH2 mutations in cholangiocarcinoma (CCA).
Design: DNA was extracted from 94 paraffin-embedded CCA resection specimens (67 intrahepatic and 27 extrahepatic). Pyrosequencing was performed using a Qiagen PyroMark Q24 system (Valencia, CA), assessing for mutations in codons 132 of IDH1 and codons 140 and 172 of IDH2. Identified mutations were confirmed by Sanger sequencing. The association between the occurrence of mutations in IDH1 and IDH2 and clinicopathologic results were examined using the Chi-square and Fisher's exact tests, as appropriate. Kaplan-Meier curves were plotted and survival was compared using the logrank value. All reported P-values were two-sided and P-values less than 0.05 were considered statistically significant.
Results: Mutations were detected in 21 (22%) of the 94 evaluated specimens including 14 IDH1 and 7 IDH2 mutations. IDH1 mutations included R132C (n=9), R132S (n=2), R132G (n=2), and R132L (n=1). The 7 IDH2 mutations included R172K (n=5), R172M (n=1) and R172G (n=1). Mutations were more frequently observed in intrahepatic CCA compared to extrahepatic CCA (28% vs. 7%, respectively; P=0.030). There were no significant differences in the frequency of IDH1/2 mutations when compared to age, gender, lymph node metastasis, or associated PSC status. Patients with an IDH1/2 gene mutation appeared to have better overall survival a year following surgical resection when compared to patients without an IDH1/2 mutation (95% vs. 83%, respectively), however, the overall median survival was not significantly different (P=0.338).
Conclusions: The results of this study show for the first time that IDH1 and IDH2 genes are mutated in CCA. The results of this study are encouraging because it identifies a potential biomarker for earlier detection of CCA and a new target for genotype-directed therapeutic trials. Additional studies with larger cohorts are needed to determine whether patients with IDH1/2 mutations are clinically distinct from CCA patients without an IDH1/2 mutation.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 136, Tuesday Morning