Genetic profiling of intrahepatic cholangiocarcinoma

TY - JOUR

T1 - Genetic profiling of intrahepatic cholangiocarcinoma

AU - Andersen, Jesper Bøje

AU - Thorgeirsson, Snorri S

PY - 2012/5

Y1 - 2012/5

N2 - Purpose of Review: Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. Recent Findings: In comparison with other cancers, genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study, samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. Summary: We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single-gene studies will also be discussed.

AB - Purpose of Review: Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. Recent Findings: In comparison with other cancers, genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study, samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. Summary: We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single-gene studies will also be discussed.

KW - Anti-Inflammatory Agents

KW - Cholangiocarcinoma

KW - DNA Mutational Analysis

KW - Drug Therapy, Combination

KW - Female

KW - Gene Expression Profiling

KW - Genes, ras

KW - Genome-Wide Association Study

KW - Humans

KW - Liver Neoplasms

KW - Male

KW - Mutation

KW - Patient Selection

KW - Prognosis

KW - Pyrazoles

KW - Pyrimidines

KW - Risk Factors

U2 - 10.1097/MOG.0b013e3283523c7e

DO - 10.1097/MOG.0b013e3283523c7e

M3 - Review

C2 - 22395571

SN - 0267-1379

VL - 28

SP - 266

EP - 272

JO - Current Opinion in Gastroenterology

JF - Current Opinion in Gastroenterology

IS - 3

ER -