Faculty Collaboration Database

Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets. Ann Surg Oncol 2014 Nov;21(12):3827-34

Date

06/04/2014

Pubmed ID

24889489

Pubmed Central ID

PMC4324507

DOI

10.1245/s10434-014-3828-x

Scopus ID

2-s2.0-84918820210 (requires institutional sign-in at Scopus site)   124 Citations

Abstract

BACKGROUND: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

METHODS: Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

RESULTS: The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

CONCLUSIONS: Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

Author List

Zhu AX, Borger DR, Kim Y, Cosgrove D, Ejaz A, Alexandrescu S, Groeschl RT, Deshpande V, Lindberg JM, Ferrone C, Sempoux C, Yau T, Poon R, Popescu I, Bauer TW, Gamblin TC, Gigot JF, Anders RA, Pawlik TM

Author

Thomas Clark Gamblin MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Bile Duct Neoplasms
Bile Ducts, Intrahepatic
Biomarkers, Tumor
Cholangiocarcinoma
Combined Modality Therapy
Female
Follow-Up Studies
Gene Expression Profiling
Genomics
Humans
Lymphatic Metastasis
Male
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Invasiveness
Neoplasm Recurrence, Local
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Prognosis
Real-Time Polymerase Chain Reaction