Keun Soo Ahn1, Daniel O'Brien2, Yu Na Kang3, Taofic Mounajjed4, Yong Hoon Kim1, Tae-Seok Kim1, Jean-Pierre A Kocher2, Loretta K Allotey5,6, Mitesh J Borad7, Lewis R Roberts8, Koo Jeong Kang9. 1. Department of Surgery, Dongsan Medical Center, School of Medicine, Keimyung University, 56 Dalseong-ro, Jung-gu, Daegu, 700-712, Republic of Korea. 2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA. 3. Department of Pathology, Dongsan Medical Center, Keimyung University, Jung-gu, 42601, Daegu, Republic of Korea. 4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. 5. Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. 6. University of Minnesota Medical School, Minneapolis, MN, 55455, USA. 7. Division of Hematology and Medical Oncology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA. Borad.Mitesh@mayo.edu. 8. Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. roberts.lewis@mayo.edu. 9. Department of Surgery, Dongsan Medical Center, School of Medicine, Keimyung University, 56 Dalseong-ro, Jung-gu, Daegu, 700-712, Republic of Korea. kjkang@dsmc.or.kr.
Abstract
BACKGROUND: Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes. METHODS: We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation. RESULTS: Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine. CONCLUSIONS: Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment.
BACKGROUND: Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes. METHODS: We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation. RESULTS:Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine. CONCLUSIONS: Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment.
Authors: Xin Luo; Nellie A Campbell; Li He; Daniel R O'Brien; Mark S Singer; Hassan Lemjabbar-Alaoui; Keun Soo Ahn; Rory Smoot; Michael S Torbenson; Steven D Rosen; Lewis R Roberts Journal: Hepatology Date: 2021-05-24 Impact factor: 17.298
Authors: Xiwei Ding; Tianlu Huang; Chunyan Peng; Keun Soo Ahn; Jesper B Andersen; Monika Lewinska; Yu Cao; Guifang Xu; Gang Chen; Bo Kong; Helmut Friess; Shanshan Shen; Lewis R Roberts; Lei Wang; Xiaoping Zou Journal: J Cancer Date: 2020-02-03 Impact factor: 4.207