A Transcriptomic Signature for Risk-Stratification and Recurrence Prediction in Intrahepatic Cholangiocarcinoma.
Adaptor Proteins, Signal Transducing
/ genetics
Adult
Aged
Aged, 80 and over
Antigens, CD
/ genetics
Bile Duct Neoplasms
/ genetics
Bile Ducts, Intrahepatic
Cadherins
/ genetics
Cdc20 Proteins
/ genetics
Cell Cycle Proteins
/ genetics
Cholangiocarcinoma
/ genetics
Chromosomal Proteins, Non-Histone
/ genetics
Cytoskeletal Proteins
/ genetics
Female
Humans
Male
Membrane Proteins
/ genetics
Middle Aged
N-Glycosyl Hydrolases
/ genetics
Neoplasm Recurrence, Local
/ genetics
Nuclear Proteins
/ genetics
Proportional Hazards Models
Risk Assessment
Survivin
/ genetics
Transcriptome
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
06
01
2021
received:
20
10
2020
accepted:
23
02
2021
pubmed:
17
3
2021
medline:
14
1
2022
entrez:
16
3
2021
Statut:
ppublish
Résumé
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. 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. We report a transcriptomic signature for risk-stratification and recurrence prediction that is superior to currently used clinicopathological features in patients with ICC.
Sections du résumé
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.
Identifiants
pubmed: 33725402
doi: 10.1002/hep.31803
pmc: PMC8443691
mid: NIHMS1684910
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antigens, CD
0
BIRC5 protein, human
0
CDH2 protein, human
0
CENPW protein, human
0
Cadherins
0
Cdc20 Proteins
0
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
Cytoskeletal Proteins
0
MAD2L1BP protein, human
0
Membrane Proteins
0
Nuclear Proteins
0
POC1A protein, human
0
Survivin
0
junctophilin
0
CDC20 protein, human
156288-95-8
N-Glycosyl Hydrolases
EC 3.2.2.-
NEIL3 protein, human
EC 3.2.2.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1371-1383Subventions
Organisme : NCI NIH HHS
ID : R01 CA202797
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA184792
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA187956
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181572
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA072851
Pays : United States
Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
Références
Cancer. 2011 May 15;117(10):2170-7
pubmed: 21523730
Cell Physiol Biochem. 2016;38(4):1563-74
pubmed: 27073840
Hepatology. 2019 Oct;70(4):1246-1261
pubmed: 30972782
Hepatogastroenterology. 2012 Sep;59(118):1765-8
pubmed: 22369746
Eur J Surg Oncol. 2019 Aug;45(8):1432-1438
pubmed: 30914290
Hepatogastroenterology. 2002 Mar-Apr;49(44):311-6
pubmed: 11995440
Radiother Oncol. 2018 Sep;128(3):575-583
pubmed: 29801723
J Gastrointest Surg. 2012 Apr;16(4):874-81
pubmed: 21975686
Liver Int. 2018 Jan;38(1):113-124
pubmed: 28608943
JAMA. 2005 Jun 1;293(21):2609-17
pubmed: 15928282
Medicine (Baltimore). 2019 Feb;98(5):e14013
pubmed: 30702559
J Am Coll Surg. 2009 Jan;208(1):134-47
pubmed: 19228515
Cancer Sci. 2019 Oct;110(10):3197-3203
pubmed: 31361379
Can J Surg. 2018 Feb;61(1):19-27
pubmed: 29368673
Cell Biochem Funct. 2010 Jun;28(4):249-57
pubmed: 20517887
Surgery. 2013 Jun;153(6):811-8
pubmed: 23499016
J Clin Oncol. 2019 Apr 20;37(12):1015-1027
pubmed: 30856044
Ann Surg. 2019 May;269(5):879-886
pubmed: 29240008
J Surg Oncol. 2018 Mar;117(3):380-388
pubmed: 28940411
Ann Oncol. 2006 Jun;17 Suppl 7:vii68-72
pubmed: 16760298
J Surg Oncol. 2014 Aug;110(2):163-70
pubmed: 24676600
Ann Surg. 2008 Jul;248(1):84-96
pubmed: 18580211
J Natl Compr Canc Netw. 2017 May;15(5):563-573
pubmed: 28476736
Ann Surg. 2011 Nov;254(5):824-29; discussion 830
pubmed: 22042474
Gastroenterology. 2018 Mar;154(4):844-848.e7
pubmed: 29199088
Br J Surg. 2012 Dec;99(12):1711-7
pubmed: 23132419
Ann Surg Oncol. 2019 Aug;26(8):2549-2557
pubmed: 31020501
Lancet. 2005 Oct 8;366(9493):1303-14
pubmed: 16214602
JAMA Surg. 2014 Jun;149(6):565-74
pubmed: 24718873
Ann Surg Oncol. 2015 Dec;22 Suppl 3:S1133-9
pubmed: 25976862
J Clin Oncol. 2000 Mar;18(5):1094-101
pubmed: 10694562
Genetics. 1973 Jun;74(2):267-86
pubmed: 17248617
Br J Surg. 2018 Jun;105(7):839-847
pubmed: 28858392
BMC Gastroenterol. 2018 Dec 4;18(1):180
pubmed: 30514231
Updates Surg. 2010 Aug;62(1):11-9
pubmed: 20845096
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Ann Surg Oncol. 2016 Jan;23(1):235-43
pubmed: 26059651
Oncologist. 2008 Apr;13(4):415-23
pubmed: 18448556
Br J Cancer. 2007 Mar 26;96(6):896-902
pubmed: 17325704
Cell Cycle. 2012 Jul 15;11(14):2729-38
pubmed: 22785131
J Gastroenterol. 2006 Sep;41(9):893-900
pubmed: 17048054
J Surg Oncol. 2019 Jan;119(1):21-29
pubmed: 30466151
Br J Surg. 2018 Jun;105(7):848-856
pubmed: 29193010
Ann Surg Oncol. 2009 Apr;16(4):792-4
pubmed: 19190964
Nat Med. 1997 Aug;3(8):917-21
pubmed: 9256286
Medicine (Baltimore). 2016 Jul;95(28):e4133
pubmed: 27428200
World J Gastrointest Oncol. 2013 Apr 15;5(4):81-7
pubmed: 23671735
Hepatobiliary Pancreat Dis Int. 2019 Apr;18(2):110-116
pubmed: 30470543
J Cancer. 2018 Aug 6;9(17):3117-3128
pubmed: 30210635
J Hepatol. 2019 Jul;71(1):104-114
pubmed: 30910538
N Engl J Med. 2010 Apr 8;362(14):1273-81
pubmed: 20375404
J Clin Oncol. 2011 Aug 10;29(23):3140-5
pubmed: 21730269