Frequency of TERT promoter mutations in primary tumors of the liver

TY - JOUR

T1 - Frequency of TERT promoter mutations in primary tumors of the liver

AU - Quaas, Alexander

AU - Oldopp, Theresa

AU - Tharun, Lars

AU - Klingenfeld, Catina

AU - Krech, Till

AU - Sauter, Guido

AU - Grob, Tobias J

PY - 2014/12

Y1 - 2014/12

N2 - Transcriptional regulation of the TERT gene is a major cause of the cancer-specific increase in telomerase activity. Recently, frequent somatic mutations in the TERT promoter have been described in several tumor entities such as melanoma, glioblastoma, bladder cancer, and hepatocellular carcinoma. By generating a putative consensus binding site for ETS transcription factors within the TERT promoter, these mutations are predicted to increase promoter activity and TERT transcription. In order to improve the understanding of the role of TERT promoter mutation in liver tumorigenesis, the mutational status of the TERT promoter was analyzed in 78 hepatocellular carcinomas, 15 hepatocellular adenomas, and 52 intrahepatic cholangiocarciomas. The promoter region of TERT was screened for the two hotspot mutations using PCR and restriction fragment length analysis, utilizing the introduction of novel restriction sites by the somatic mutations. TERT promoter mutation was found in 37 of 78 hepatocellular carcinomas (47 %) and was restricted to the -124C>T mutation. Frequency of mutations was associated with grade of differentiation ranging from 39 % in well-differentiated tumors to 73 % in high-grade hepatocellular carcinomas. TERT promoter mutations were not found in 15 hepatocellular adenomas and 52 intrahepatic cholangiocarcinomas. These data show that TERT promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma known at this time. The striking predominance of the -124C>T mutation compared with other tumor entities suggest a biological difference of the two hotspot mutations. Analysis of TERT promoter mutation might become a diagnostic tool distinguishing hepatocellular adenoma from well-differentiated hepatocellular carcinoma.

AB - Transcriptional regulation of the TERT gene is a major cause of the cancer-specific increase in telomerase activity. Recently, frequent somatic mutations in the TERT promoter have been described in several tumor entities such as melanoma, glioblastoma, bladder cancer, and hepatocellular carcinoma. By generating a putative consensus binding site for ETS transcription factors within the TERT promoter, these mutations are predicted to increase promoter activity and TERT transcription. In order to improve the understanding of the role of TERT promoter mutation in liver tumorigenesis, the mutational status of the TERT promoter was analyzed in 78 hepatocellular carcinomas, 15 hepatocellular adenomas, and 52 intrahepatic cholangiocarciomas. The promoter region of TERT was screened for the two hotspot mutations using PCR and restriction fragment length analysis, utilizing the introduction of novel restriction sites by the somatic mutations. TERT promoter mutation was found in 37 of 78 hepatocellular carcinomas (47 %) and was restricted to the -124C>T mutation. Frequency of mutations was associated with grade of differentiation ranging from 39 % in well-differentiated tumors to 73 % in high-grade hepatocellular carcinomas. TERT promoter mutations were not found in 15 hepatocellular adenomas and 52 intrahepatic cholangiocarcinomas. These data show that TERT promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma known at this time. The striking predominance of the -124C>T mutation compared with other tumor entities suggest a biological difference of the two hotspot mutations. Analysis of TERT promoter mutation might become a diagnostic tool distinguishing hepatocellular adenoma from well-differentiated hepatocellular carcinoma.

KW - Adenoma

KW - Adolescent

KW - Adult

KW - Aged

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Carcinoma, Hepatocellular

KW - Child

KW - Cholangiocarcinoma

KW - DNA Mutational Analysis

KW - Female

KW - Humans

KW - Liver Neoplasms

KW - Male

KW - Middle Aged

KW - Mutation

KW - Polymerase Chain Reaction

KW - Polymorphism, Restriction Fragment Length

KW - Promoter Regions, Genetic

KW - Telomerase

KW - Young Adult

U2 - 10.1007/s00428-014-1658-7

DO - 10.1007/s00428-014-1658-7

M3 - SCORING: Journal article

C2 - 25267585

VL - 465

SP - 673

EP - 677

JO - VIRCHOWS ARCH

JF - VIRCHOWS ARCH

SN - 0945-6317

IS - 6

ER -