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.
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References
Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40:472–7.
Poultsides GA, Zhu AX, Choti MA, et al. Intrahepatic cholangiocarcinoma. Surg Clin North Am. 2010;90:817–37.
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.
Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–40.
Sia D, Tovar V, Moeini A, et al. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013;32:4861–70.
Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17:72–9.
Tannapfel A, Sommerer F, Benicke M, et al. Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J Pathol. 2002;197:624–31.
Voss JS, Holtegaard LM, Kerr SE, et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol. 2013;44:1216–22.
Xu RF, Sun JP, Zhang SR, et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother. 2011;65:22–6.
Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45:1470–3.
Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32:3091–100.
Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142:1021–31.e15.
Dias-Santagata D, Akhavanfard S, David SS, et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med. 2010;2:146–58.
Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer. 2013;119:4137–44.
Bazan V, Agnese V, Corsale S, et al. Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell’Italia Meridionale (GOIM) prospective study. Ann Oncol. 2005;16(Suppl 4):iv50–5.
Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the “RASCAL II” study. Br J Cancer. 2001;85:692–6.
Woo HG, Park ES, Thorgeirsson SS, et al. Exploring genomic profiles of hepatocellular carcinoma. Mol Carcinog. 2011;50:235–43.
Lee S, Lee HJ, Kim JH, et al. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–8.
Minguez B, Tovar V, Chiang D, et al. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol. 2009;25:186–94.
Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008;10:77–82.
Robertson S, Hyder O, Dodson R, et al. The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome. Hum Pathol. 2013;44:2768–73.
Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut. 2000;47:721–7.
Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144:829–40.
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.
Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.
Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.
Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43:1552–8.
Chan-On W, Nairismagi ML, Ong CK, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–8.
Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat Genet. 2012;44:690–3.
Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636–47.
Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012;28:266–72.
Riener MO, Bawohl M, Clavien PA, et al. Rare PIK3CA hotspot mutations in carcinomas of the biliary tract. Genes Chromosomes Cancer. 2008;47:363–7.
Ross JS, Wang J, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinoma revealed by next-generation sequencing. Oncologist. 2014;19:235–42.
Acknowledgment
We thank Kenneth C. Fan, Hector U. Lopez, and Christina R. Matulis for their technical assistance and Daniel J. Harris for data collection. Supported in part by Agios.
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The authors declare no conflict of interest.
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Supplementary Fig. 1
Overall survival stratified by a no identified mutation versus “any” mutation cases b no identified mutation vs. KRAS or BRAF mutant cases c noidentified mutation versuss PIK3CA or PTEN mutant cases d no identified mutation versus IDH1 or IDH. Supplementary material 6 (TIFF 1521 kb)
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Zhu, A.X., Borger, D.R., Kim, Y. et al. Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets. Ann Surg Oncol 21, 3827–3834 (2014). https://doi.org/10.1245/s10434-014-3828-x
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DOI: https://doi.org/10.1245/s10434-014-3828-x