Abstract 3172: Comprehensive analysis of intrahepatic cholangiocarcinoma based on viral infections and mutational status in the IDH1/2 and KRAS genes
Authors: Yasui Kazuya , Nagasaka Takeshi , Umeda Yuzo , Fuji Tomokazu , Taniguchi Fumitaka , Toshima Toshiaki , Kimura Keisuke , Kawai Takashi , Mori Yoshiko , Tazawa Hiroshi , Yagi Takahito , Goel Ajay , Fujiwara Toshiyoshi 
Published: July 2016

Abstract
Background: Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with poor prognosis and limited therapeutic options. Recently comprehensive genetic profiles have elucidated novel fusion genes and somatic mutations. Although somatic mutations in the isocitrate dehydrogenase (IDH) and KRAS gene were frequently found in ICC, the clinical features of this malignancy with mutations in these genes remain unclear.
Materials and Methods: A cohort of 49 patients with ICC who underwent curative resection from 2000 to 2013 at Okayama University Hospital were enrolled and analyzed. KRAS (exon2), IDH1 (codon132), and IDH2 (codon172 and codon140) mutations were confirmed by Sanger sequencing. Associations between the mutational profiles of these genes and clinic-pathological features were investigated. Kaplan-Meier curves were plotted, and survival rates were compared using the log-rank analysis.
Results: KRAS mutations were observed in twelve ICC patients (24.5%, KRAS-mutant). IDH mutations were found in eight patients (16.3%); five patients harbored IDH1 mutations and three patients harbored IDH2 mutations (IDH1/2-mutant). Among three patients with IDH2 mutations, a rare IDH2 R140L was identified. One patient harbored both KRAS G12A and IDH2 R172K mutations (classified as KRAS-mutant). The rest of 30 ICCs harbored no mutation in either KRAS or IDH1/2 gene, thus categorized as Wild-type. Infection of Hepatitis B (HBV) or C (HCV) was observed in 10 ICCs (6 ICCs were HBV-positive and 4 ICCs were HCV-positive). Of 10 ICCs with viral infection, only two ICCs harbored KRAS mutations (categorized as virus-infected) and eight ICCs with viral infection harbored no mutation in KRAS and IDH1/2 genes. Finally, ICCs were divided into four subsets; viral-infected, KRAS-mutant, IDH1/2-mutant, and ‘others’). With regard to clinic-pathological features, lymph node metastasis was more frequently observed in KRAS-mutant (p = 0.039) compared with the others. IDH1/2 -mutant were more frequently observed in mass-forming type (p = 0.047). By survival analysis, 3-years survival rate was 85.7% in IDH1/2-mutant, 58.3% in the others, 36.3% in viral-infected, and 22.2% in KRAS-mutant, respectively (p = 0.05). Thus, our cohort suggests that IDH1/2, as well as KRAS mutations, have the potential to serve as prognostic biomarkers in ICC.
Conclusion: We conclude that not only viral infections, but also IDH1/2 and KRAS mutations could be potential predictive markers for the identification of good and worse prognosis in ICCs. Hence the mutational profiles of these genes provide an attractive rationale for developing a molecular signature for the development of non-invasive screening for ICCs in future.
Citation Format: Kazuya Yasui, Takeshi Nagasaka, Yuzo Umeda, Tomokazu Fuji, Fumitaka Taniguchi, Toshiaki Toshima, Keisuke Kimura, Takashi Kawai, Yoshiko Mori, Hiroshi Tazawa, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara. Comprehensive analysis of intrahepatic cholangiocarcinoma based on viral infections and mutational status in the IDH1/2 and KRAS genes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3172.