A Transcriptomic Signature for Risk-Stratification and Recurrence Prediction in Intrahepatic Cholangiocarcinoma
Yuma Wada
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Surgery, Tokushima University, Tokushima, Japan
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA
Search for more papers by this authorMitsuo Shimada
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorKensuke Yamamura
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Search for more papers by this authorTakeo Toshima
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorJasjit K Banwait
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Search for more papers by this authorYuji Morine
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorTetsuya Ikemoto
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorYu Saito
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorHideo Baba
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Search for more papers by this authorMasaki Mori
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Ajay Goel
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Ajay Goel, Ph.D.
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope
Biomedical Research Center
1218 S. Fifth Avenue, Suite 2226
Monrovia, CA 91016
E-mail: [email protected]
Tel.: +1-626-218-3452
Search for more papers by this authorYuma Wada
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Surgery, Tokushima University, Tokushima, Japan
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA
Search for more papers by this authorMitsuo Shimada
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorKensuke Yamamura
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Search for more papers by this authorTakeo Toshima
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorJasjit K Banwait
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Search for more papers by this authorYuji Morine
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorTetsuya Ikemoto
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorYu Saito
Department of Surgery, Tokushima University, Tokushima, Japan
Search for more papers by this authorHideo Baba
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Search for more papers by this authorMasaki Mori
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Ajay Goel
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Ajay Goel, Ph.D.
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope
Biomedical Research Center
1218 S. Fifth Avenue, Suite 2226
Monrovia, CA 91016
E-mail: [email protected]
Tel.: +1-626-218-3452
Search for more papers by this authorAbstract
Background and Aims
Tumor recurrence is frequent even in intrahepatic cholangiocarcinoma (ICC), and improved strategies are needed to identify patients at highest risk for such recurrence. We performed genome-wide expression profile analyses to discover and validate a gene signature associated with recurrence in patients with ICC.
Approach and Results
For biomarker discovery, we analyzed genome-wide transcriptomic profiling in ICC tumors from two public data sets: The Cancer Genome Atlas (n = 27) and GSE107943 (n = 28). We identified an eight-gene panel (BIRC5 [baculoviral IAP repeat containing 5], CDC20 [cell division cycle 20], CDH2 [cadherin 2], CENPW [centromere protein W], JPH1 [junctophilin 1], MAD2L1 [mitotic arrest deficient 2 like 1], NEIL3 [Nei like DNA glycosylase 3], and POC1A [POC1 centriolar protein A]) that robustly identified patients with recurrence in the discovery (AUC = 0.92) and in silico validation cohorts (AUC = 0.91). We next analyzed 241 specimens from patients with ICC (training cohort, n = 64; validation cohort, n = 177), followed by Cox proportional hazard regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model for recurrence in ICC. We subsequently trained this transcriptomic panel in a clinical cohort (AUC = 0.89; 95% confidence interval [CI] = 0.79-0.95), followed by evaluating its performance in an independent validation cohort (AUC = 0.86; 95% CI = 0.80-0.90). By combining our transcriptomic panel with various clinicopathologic features, we established a risk-stratification model that was significantly superior for the identification of recurrence (AUC = 0.89; univariate HR = 6.08, 95% CI = 3.55-10.41, P < 0.01; and multivariate HR = 3.49, 95% CI = 1.81-6.71, P < 0.01). The risk-stratification model identified potential recurrence in 85% of high-risk patients and nonrecurrence in 76% of low-risk patients, which is dramatically superior to currently used pathological features.
Conclusions
We report a transcriptomic signature for risk-stratification and recurrence prediction that is superior to currently used clinicopathological features in patients with ICC.
Supporting Information
Filename | Description |
---|---|
hep31803-sup-0001-Supinfo.pdfPDF document, 187.6 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Aljiffry M, Abdulelah A, Walsh M, Peltekian K, Alwayn I, Molinari M. Evidence-based approach to cholangiocarcinoma: a systematic review of the current literature. J Am Coll Surg 2009; 208: 134-147.
- 2Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P, El-Serag HB, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol 2019; 71: 104-114.
- 3Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005; 366: 1303-1314.
- 4Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg 2014; 149: 565-574.
- 5Amini N, Ejaz A, Spolverato G, Kim Y, Herman JM, Pawlik TM. Temporal trends in liver-directed therapy of patients with intrahepatic cholangiocarcinoma in the United States: a population-based analysis. J Surg Oncol 2014; 110: 163-170.
- 6Farges O, Fuks D, Boleslawski E, Le Treut YP, Castaing D, Laurent A, Ducerf C, et al. Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann Surg 2011; 254: 824-829; discussion 830.
- 7Hyder O, Hatzaras I, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery 2013; 153: 811-818.
- 8Spolverato G, Kim Y, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol 2016; 23: 235-243.
- 9Sulpice L, Rayar M, Boucher E, Pracht M, Meunier B, Boudjema K. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg 2012; 99: 1711-1717.
- 10Zhang XF, Beal EW, Bagante F, Chakedis J, Weiss M, Popescu I, et al. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg 2018; 105: 848-856.
- 11Hoehn RS, Wima K, Ertel AE, Meier A, Ahmad SA, Shah SA, et al. Adjuvant chemotherapy and radiation therapy is associated with improved survival for patients with extrahepatic cholangiocarcinoma. Ann Surg Oncol 2015; 22(Suppl 3): S1133-S1139.
- 12Wirasorn K, Ngamprasertchai T, Chindaprasirt J, Sookprasert A, Khantikaew N, Pakkhem A, et al. Prognostic factors in resectable cholangiocarcinoma patients: carcinoembryonic antigen, lymph node, surgical margin and chemotherapy. World J Gastrointest Oncol 2013; 5: 81-87.
- 13Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, et al. NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017. J Natl Compr Canc Netw 2017; 15: 563-573.
- 14Lin Y-K, Hsieh M-C, Wang W-W, Lin Y-C, Chang W-W, Chang C-L, et al. Outcomes of adjuvant treatments for resectable intrahepatic cholangiocarcinoma: chemotherapy alone, sequential chemoradiotherapy, or concurrent chemoradiotherapy. Radiother Oncol 2018; 128: 575-583.
- 15Shroff RT, Kennedy EB, Bachini M, Bekaii-Saab T, Crane C, Edeline J, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol 2019; 37: 1015-1027.
- 16de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011; 29: 3140-3145.
- 17Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008; 248: 84-96.
- 18Farges O, Fuks D, Le Treut YP, Azoulay D, Laurent A, Bachellier P, Nuzzo G, et al. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: by the AFC-IHCC-2009 study group. Cancer 2011; 117: 2170-2177.
- 19Ma KW, Cheung TT, She WH, Chok KSH, Chan ACY, Ng IOL, et al. The effect of wide resection margin in patients with intrahepatic cholangiocarcinoma: a single-center experience. Medicine (Baltimore) 2016; 95:e4133.
- 20Chan KM, Tsai CY, Yeh CN, Yeh TS, Lee WC, Jan YY, et al. Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence. BMC Gastroenterol 2018; 18: 180.
- 21He C, Zhang Y, Song Y, Wang J, Xing K, Lin X, et al. Preoperative CEA levels are supplementary to CA19-9 levels in predicting prognosis in patients with resectable intrahepatic cholangiocarcinoma. J Cancer 2018; 9: 3117-3128.
- 22Hu L-S, Zhang X-F, Weiss M, Popescu I, Marques HP, Aldrighetti L, et al. Recurrence patterns and timing courses following curative-intent resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2019; 26: 2549-2557.
- 23Poon RT. Differentiating early and late recurrences after resection of HCC in cirrhotic patients: implications on surveillance, prevention, and treatment strategies. Ann Surg Oncol 2009; 16: 792-794.
- 24Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 2000; 18: 1094-1101.
- 25Miyata T, Yamashita YI, Yoshizumi T, Shiraishi M, Ohta M, Eguchi S, et al. CXCL12 expression in intrahepatic cholangiocarcinoma is associated with metastasis and poor prognosis. Cancer Sci 2019; 110: 3197-3203.
- 26Chen LP, Li C, Wang C, Wen TF, Yan LN, Li B. Predictive factors of recurrence for patients with intrahepatic cholangiocarcinoma after hepatectomy. Hepatogastroenterology 2012; 59: 1765-1768.
- 27Hanazaki K, Kajikawa S, Shimozawa N, Shimada K, Hiraguri M, Koide N, et al. Prognostic factors of intrahepatic cholangiocarcinoma after hepatic resection: univariate and multivariate analysis. Hepatogastroenterology 2002; 49: 311-316.
- 28Miwa S, Miyagawa S, Kobayashi A, Akahane Y, Nakata T, Mihara M, et al. Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery. J Gastroenterol 2006; 41: 893-900.
- 29Nuzzo G, Giuliante F, Ardito F, De Rose AM, Vellone M, Clemente G, et al. Intrahepatic cholangiocarcinoma: prognostic factors after liver resection. Updates Surg 2010; 62: 11-19.
- 30Kneuertz PJ, Cosgrove DP, Cameron AM, Kamel IR, Geschwind JF, Herman JM, et al. Multidisciplinary management of recurrent hepatocellular carcinoma following liver transplantation. J Gastrointest Surg 2012; 16: 874-881.
- 31Ozawa T, Kandimalla R, Gao F, Nozawa H, Hata K, Nagata H, et al. A MicroRNA signature associated with metastasis of T1 colorectal cancers to lymph nodes. Gastroenterology 2018; 154: 844-848.e847.
- 32Sonohara F, Gao F, Iwata N, Kanda M, Koike M, Takahashi N, et al. Genome-wide discovery of a novel gene-expression signature for the identification of lymph node metastasis in esophageal squamous cell carcinoma. Ann Surg 2019; 269: 879-886.
- 33Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402-408.
- 34Eamer GJ, Clement F, Pederson JL, Churchill TA, Khadaroo RG. Analysis of postdischarge costs following emergent general surgery in elderly patients. Can J Surg 2018; 61: 19-27.
- 35Studdert DM, Mello MM, Sage WM, DesRoches CM, Peugh J, Zapert K, et al. Defensive medicine among high-risk specialist physicians in a volatile malpractice environment. JAMA 2005; 293: 2609-2617.
- 36Hu L-S, Weiss M, Popescu I, Marques HP, Aldrighetti L, Maithel SK, et al. Impact of microvascular invasion on clinical outcomes after curative-intent resection for intrahepatic cholangiocarcinoma. J Surg Oncol 2019; 119: 21-29.
- 37Kim BH, Kim E, Kim K, Jang JY, Kim SW, Oh DY, et al. The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma. J Surg Oncol 2018; 117: 380-388.
- 38Le Roy B, Gelli M, Pittau G, Allard M-A, Pereira B, Serji B, et al. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg 2018; 105: 839-847.
- 39Yadav S, Xie H, Bin-Riaz I, Sharma P, Durani U, Goyal G, et al. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: a propensity score matched analysis. Eur J Surg Oncol 2019; 45: 1432-1438.
- 40Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96: 896-902.
- 41Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist 2008; 13: 415-423.
- 42Verderame F, Russo A, Di Leo R, Badalamenti G, Santangelo D, Cicero G, Valerio MR, et al. Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers. Ann Oncol 2006; 17(Suppl 7): vii68-vii72.
- 43Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-1281.
- 44Ma KW, Cheung TT, Leung B, She BWH, Chok KSH, Chan ACY, et al. Adjuvant chemotherapy improves oncological outcomes of resectable intrahepatic cholangiocarcinoma: a meta-analysis. Medicine (Baltimore) 2019; 98:e14013.
- 45Wang ML, Ke ZY, Yin S, Liu CH, Huang Q. The effect of adjuvant chemotherapy in resectable cholangiocarcinoma: a meta-analysis and systematic review. Hepatobiliary Pancreat Dis Int 2019; 18: 110-116.
- 46Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917-921.
- 47Lozano E, Macias RIR, Monte MJ, Asensio M, Carmen S, Sanchez-Vicente L, et al. Causes of hOCT1-dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor-selective gene therapy. Hepatology 2019; 70: 1246-1261.
- 48Chen Z, Yu Y, Fu D, Li Z, Niu X, Liao M, et al. Functional roles of PC-PLC and Cdc20 in the cell cycle, proliferation, and apoptosis. Cell Biochem Funct 2010; 28: 249-257.
- 49Hartwell LH, Mortimer RK, Culotti J, Culotti M. Genetic control of the cell division cycle in yeast. Part V: Genetic analysis of cdc mutants. Genetics 1973; 74: 267-286.
- 50Yamanaka S, Campbell NR, An F, Kuo SC, Potter JJ, Mezey E, et al. Coordinated effects of microRNA-494 induce G₂/M arrest in human cholangiocarcinoma. Cell Cycle 2012; 11: 2729-2738.
- 51Ma T, Zhao YE, Wei KE, Yao G, Pan C, Liu B, et al. MicroRNA-124 functions as a tumor suppressor by regulating CDH2 and epithelial-mesenchymal transition in non-small cell lung cancer. Cell Physiol Biochem 2016; 38: 1563-1574.
- 52Rhee H, Ko JE, Chung T, Jee BA, Kwon SM, Nahm JH, et al. Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma. Liver Int 2018; 38: 113-124.
Author names in bold designate shared co-first authorship.