Diagnostic value of cell-free DNA to biliary tract cancers: a meta-analysis

doi:10.3969/j.issn.1674-8115.2023.09.012

Abstract

Abstract:

Objective ·To comprehensively evaluate the diagnostic accuracy of cell-free DNA (cfDNA) to biliary tract cancer (BTC), and provide a basis for better clinical application. Methods ·Clinical studies on the diagnostic value of cfDNA to BTC were collected by searching eight databases from inception to April 2023. The studies were selected according to the inclusion and exclusion criteria, and then data was extracted. The threshold effects were assessed with Spearman′s rank correlation analysis, and heterogeneity among the included studies was analyzed by using Cochran′s Q test and I² test. A bivariate mixed-effects model was fitted, and statistics such as overall sensitivity, specificity, and area under the curve (AUC) were calculated to determine the diagnostic performance. The subgroup analyses were carried out based on the study type, sample size, detection method, sample source, and diagnostic reference standard. Results ·A total of 28 diagnosis tests were included, all of which were evaluated as medium-high quality by using Diagnostic Accuracy Studies Tool Version 2 (QUADAS-2). The presence of threshold effects was found by using the Spearman rank correlation analysis. The pooled sensitivity was 0.80 (95%CI 0.67?0.88), and specificity was 0.96 (95%CI 0.92?0.98), positive likelihood ratio (PLR) was 22.7 (95%CI 9.4?55.2), negative likelihood ratio (NLR) was 0.21 (95%CI 0.12?0.36), and diagnostic odds ratio (DOR) was 108 (95%CI 31?374), respectively. The AUC of the summary receiver operating characteristic (SROC) curve was 0.96 (95%CI 0.94?0.98), demonstrating the high accuracy of cfDNA in the diagnosis of BTC. The results of subgroup analyses suggested that the accuracy and sensitivity of choosing different testing methods and sample sources varied. Conclusion ·The detection of cfDNA has high sensitivity and specificity in diagnosing BTC, and is suitable for the patients suspected to be malignant after screening with imaging tests and conventional tumor markers. However, the standardization and uniformity of detection methods and sample sources still need to be further standardized by conducting clinical studies on a wider population.

Key words: meta-analysis, biliary tract cancer (BTC), cell-free DNA (cfDNA), diagnosis

CLC Number:

R735.8

YANG Yue, HE Kaiju, ZONG Jiahao, YANG Ziyi, WU Xiangsong, GONG Wei. Diagnostic value of cell-free DNA to biliary tract cancers: a meta-analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(9): 1175-1185.

Figures/Tables 13

TrendMD

References 40

1	VALLE J W, LAMARCA A, GOYAL L, et al. New horizons for precision medicine in biliary tract cancers[J]. Cancer Discov, 2017, 7(9): 943-962.
2	RIZVI S, KHAN S A, HALLEMEIER C L, et al. Cholangiocarcinoma: evolving concepts and therapeutic strategies[J]. Nat Rev Clin Oncol, 2018, 15(2): 95-111.
3	BENAVIDES M, ANTÓN A, GALLEGO J, et al. Biliary tract cancers: seom clinical guidelines[J]. Clin Transl Oncol, 2015, 17(12): 982-987.
4	EVERHART J E, RUHL C E. Burden of digestive diseases in the United States Part Ⅲ: liver, biliary tract, and pancreas[J]. Gastroenterology, 2009, 136(4): 1134-1144.
5	WAN J C M, MASSIE C, GARCIA-CORBACHO J, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA[J]. Nat Rev Cancer, 2017, 17(4): 223-238.
6	VALLE J W, KELLEY R K, NERVI B, et al. Biliary tract cancer[J]. Lancet, 2021, 397(10272): 428-444.
7	BANALES J M, MARIN J J G, LAMARCA A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(9): 557-588.
8	ROA J C, GARCÍA P, KAPOOR V K, et al. Gallbladder cancer[J]. Nat Rev Dis Primers, 2022, 8(1): 69.
9	梁后杰, 秦叔逵, 沈锋, 等. CSCO胆道系统肿瘤诊断治疗专家共识(2019年版)[J]. 临床肿瘤学杂志, 2019, 24(9): 828-838.
	LIANG H J, QIN S K, SHEN F et al. Expert consensus on diagnosis and treatment of CSCO biliary systerm tumors (2019 edition)[J]. Chinese Clinical Oncology, 2019, 24(9): 828-838.
10	VALLE J W. Advances in the treatment of metastatic or unresectable biliary tract cancer[J]. Ann Oncol, 2010, 21(Suppl 7): vii345-vii348.
11	BLECHACZ B, KOMUTA M, ROSKAMS T, et al. Clinical diagnosis and staging of cholangiocarcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(9): 512-522.
12	蔡晨, 龚伟. 胆囊癌辅助治疗的研究进展[J]. 外科理论与实践, 2021, 26(2): 167-170.
	CAI C, GONG W. Study on gallbladder cancer adjuvant therapy[J]. Surgery Theory and Practice, 2021, 26(2): 167-170.
13	LONE S N, NISAR S, MASOODI T, et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments[J]. Mol Cancer, 2022, 21(1): 79.
14	CROWLEY E, DI NICOLANTONIO F, LOUPAKIS F, et al. Liquid biopsy: monitoring cancer-genetics in the blood[J]. Nat Rev Clin Oncol, 2013, 10(8): 472-484.
15	ALIX-PANABIÈRES C, PANTEL K. Liquid biopsy: from discovery to clinical application[J]. Cancer Discov, 2021, 11(4): 858-873.
16	LEON S A, SHAPIRO B, SKLAROFF D M, et al. Free DNA in the serum of cancer patients and the effect of therapy[J]. Cancer Res, 1977, 37(3): 646-650.
17	VESSIES D C L, GREUTER M J E, VAN ROOIJEN K L, et al. Performance of four platforms for KRAS mutation detection in plasma cell-free DNA: ddpcr, Idylla, COBAS z480 and BEAMing[J]. Sci Rep, 2020, 10(1): 8122.
18	HEITZER E, ULZ P, GEIGL J B. Circulating tumor DNA as a liquid biopsy for cancer[J]. Clin Chem, 2015, 61(1): 112-123.
19	OLMEDILLAS-LÓPEZ S, GARCÍA-ARRANZ M, GARCÍA-OLMO D. Current and emerging applications of droplet digital PCR in oncology[J]. Mol Diagn Ther, 2017, 21(5): 493-510.
20	IGNATIADIS M, SLEDGE G W, JEFFREY S S. Liquid biopsy enters the clinic: implementation issues and future challenges[J]. Nat Rev Clin Oncol, 2021, 18(5): 297-312.
21	SIRAVEGNA G, MUSSOLIN B, VENESIO T, et al. How liquid biopsies can change clinical practice in oncology[J]. Ann Oncol, 2019, 30(10): 1580-1590.
22	SHEN N J, ZHANG D D, YIN L, et al. Bile cell‑free DNA as a novel and powerful liquid biopsy for detecting somatic variants in biliary tract cancer[J]. Oncol Rep, 2019, 42(2): 549-560.
23	央茂, 李永盛, 吴文广, 等. 液态活检技术在胆道肿瘤诊治中的应用进展[J]. 中华肝胆外科杂志, 2021, 27(6): 472-476.
	YANG M, LI Y S, WU W G et al. Application progress of liquid biopsy in the diagnosis and treatment of biliary tract cancer[J]. Chinese Journal of Hepatobiliary Surgery, 2021, 27(6): 472-476.
24	LIBERATI A, ALTMAN D G, TETZLAFF J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration[J]. BMJ, 2009, 339: b2700.
25	HAN J Y, AHN K S, KIM T S, et al. Liquid biopsy from bile-circulating tumor DNA in patients with biliary tract cancer[J]. Cancers, 2021, 13(18): 4581.
26	HE S, ZENG F X, YIN H H, et al. Molecular diagnosis of pancreatobiliary tract cancer by detecting mutations and methylation changes in bile samples[J]. EClinicalMedicine, 2023, 55: 101736.
27	HUA Y, SUN F Y, HU F, et al. Diagnostic value of quantification of circulating free DNA for gall bladder cancer using a chemiluminescence DNA biosensor system based on DNA G-quadruplex/hemin enzyme[J]. Transl Oncol, 2021, 14(1): 100928.
28	KINUGASA H, NOUSO K, AKO S, et al. Liquid biopsy of bile for the molecular diagnosis of gallbladder cancer[J]. Cancer Biol Ther, 2018, 19(10): 934-938.
29	KUMARI S, HUSAIN N, AGARWAL A, et al. Diagnostic value of circulating free DNA integrity and global methylation status in gall bladder carcinoma[J]. Pathol Oncol Res, 2019, 25(3): 925-936.
30	KUMARI S, MISHRA S, HUSAIN N, et al. Comparison of circulating DNA in malignant neoplasia from diverse locations: investigating a diagnostic role[J]. Indian J Pathol Microbiol, 2022, 65(1): 93-99.
31	KUMARI S, TEWARI S, HUSAIN N, et al. Quantification of circulating free DNA as a diagnostic marker in gall bladder cancer[J]. Pathol Oncol Res, 2017, 23(1): 91-97.
32	WANG X, FU X H, QIAN Z L, et al. Non-invasive detection of biliary tract cancer by low-coverage whole genome sequencing from plasma cell-free DNA: a prospective cohort study[J]. Transl Oncol, 2021, 14(1): 100908.
33	WASENANG W, CHAIYARIT P, PROUNGVITAYA S, et al. Serum cell-free DNA methylation of OPCML and HOXD9 as a biomarker that may aid in differential diagnosis between cholangiocarcinoma and other biliary diseases[J]. Clin Epigenetics, 2019, 11(1): 39.
34	WINTACHAI P, LIM J Q, TECHASEN A, et al. Diagnostic and prognostic value of circulating cell-free DNA for cholangiocarcinoma[J]. Diagnostics, 2021, 11(6): 999.
35	莫迪, 李梦雨, 李华洋, 等. CA199、CEA及cfDNA的联合检测对胆管癌的辅助诊断价值[J]. 牡丹江医学院学报, 2020, 41(3): 18-21.
	MO D, LI M Y, LI H Y, et al. Diagnostic value of combined detection of CA, CEA and plasma cell-free DNA for cholangiocarcinoma[J]. Journal of Mudanjiang Medical University, 2020, 41(3): 18-21.
36	张俊, 徐志伟, 李克. 诊断性试验meta分析的效应指标评价[J]. 中国循证医学杂志, 2013, 13(7): 890-895.
	ZHANG J, XU Z W, LI K. Evaluation on the effect index of diagnostic test[J]. Chinese Journal of Evidence-Based Medicine, 2013, 13(7): 890-895.
37	KHAN S A, TAVOLARI S, BRANDI G. Cholangiocarcinoma: epidemiology and risk factors[J]. Liver Int, 2019, 39(S1): 19-31.
38	ARRICHIELLO G, NACCA V, PARAGLIOLA F, et al. Liquid biopsy in biliary tract cancer from blood and bile samples: current knowledge and future perspectives[J]. Explor Target Antitumor Ther, 2022, 3(3): 362-374.
39	SINGH A, DWIVEDI A. Circulating miRNA and cell-free DNA as a potential diagnostic tool in early detection of biliary tract cancer: a meta-analysis[J]. Biomarkers, 2022, 27(5): 399-406.
40	龚伟, 吴向嵩, 杨自逸. 胆囊癌转化治疗模式探索与思考[J]. 中国实用外科杂志, 2022, 42(2): 163-166.
	GONG W, WU X S, YANG Z Y. Exploring novel therapeutic approach for advanced gallbladder cancer[J]. Chinese Journal of Practical Surgery, 2022, 42(2): 163-166.

Study	Study type	Country	Reference standard
HAN 2021^[25]	Prospective study	South Korea	BTC: pathological examination
HE 2023^[26]	Retrospective and prospective study	China	BTC: pathological examination; BBD: pathological examination and clinical follow-up; healthy population: pathological examination/clinical follow-up
HUA 2021^[27]	Prospective study	China	BTC: pathological examination
KINUGASA 2018^[28]	Prospective study	Japan	Pathological examination
KUMARI 2019^[29]	Retrospective study	India	Imaging/pathological examination
KUMARI 2022^[30]	Retrospective study	India	Imaging/pathological examination
KUMARI 2017^[31]	Retrospective study	India	Imaging/pathological examination
WANG 2021^[32]	Prospective study	China	Pathological examination
WASENANG 2019^[33]	Prospective study	Thailand	BTC: pathological examination
WINTACHAI 2021^[34]	Retrospective study	Thailand	Pathological examination
MO 2020^[35]	Retrospective study	China	BTC/BBD: imaging examination/pathological examination

Study	Study type	Country	Reference standard
HAN 2021^[25]	Prospective study	South Korea	BTC: pathological examination
HE 2023^[26]	Retrospective and prospective study	China	BTC: pathological examination; BBD: pathological examination and clinical follow-up; healthy population: pathological examination/clinical follow-up
HUA 2021^[27]	Prospective study	China	BTC: pathological examination
KINUGASA 2018^[28]	Prospective study	Japan	Pathological examination
KUMARI 2019^[29]	Retrospective study	India	Imaging/pathological examination
KUMARI 2022^[30]	Retrospective study	India	Imaging/pathological examination
KUMARI 2017^[31]	Retrospective study	India	Imaging/pathological examination
WANG 2021^[32]	Prospective study	China	Pathological examination
WASENANG 2019^[33]	Prospective study	Thailand	BTC: pathological examination
WINTACHAI 2021^[34]	Retrospective study	Thailand	Pathological examination
MO 2020^[35]	Retrospective study	China	BTC/BBD: imaging examination/pathological examination

Subgroup	Study/n	Sensitivity (95%CI)	Specificity (95%CI)	PLR	NLR	DOR	AUC (95%CI)
Overall	28	0.80 (0.67‒0.88)	0.96 (0.92‒0.98)	22.7	0.21	108	0.96 (0.94‒0.98)
Study type
Prospective study	16	0.74 (0.51‒0.89)	0.97 (0.93‒0.99)	26.1	0.26	99	0.97 (0.95‒0.98)
Retrospective study	10	0.86 (0.72‒0.93)	0.93 (0.73‒0.99)	12.4	0.15	81	0.95 (0.92‒0.96)
Sample size
>90	12	0.89 (0.78‒0.95)	0.96 (0.83‒0.99)	20.9	0.12	179	0.96 (0.94‒0.98)
≤90	16	0.67 (0.47‒0.83)	0.97 (0.92‒0.99)	23.9	0.34	71	0.96 (0.94‒0.97)
Method
Gene or mutation analysis	6	0.67 (0.44‒0.84)	1.00 (0.85‒1.00)	457.0	0.33	1 394	0.95 (0.93‒0.97)
qPCR	13	0.94 (0.84‒0.98)	0.98 (0.88‒1.00)	38.8	0.06	644	0.99 (0.98‒1.00)
Methylation analysis	9	0.51 (0.37‒0.65)	0.94 (0.82‒0.98)	9.2	0.52	18	0.77 (0.73‒0.81)
Sample type
Bile	4	0.70 (0.53‒0.83)	1.00 (0.67‒1.00)	511.0	0.30	1 690	0.95 (0.92‒0.96)
Serum	19	0.85 (0.66‒0.94)	0.97 (0.90‒0.99)	24.7	0.16	156	0.97 (0.96‒0.99)
Plasma	5	0.72 (0.45‒0.89)	0.92 (0.70‒0.98)	9.4	0.30	31	0.91 (0.88‒0.93)
Control type
Benign biliary disease	18	0.68 (0.54‒0.79)	0.96 (0.92‒0.99)	19.0	0.34	57	0.93 (0.91‒0.95)
Healthy population	6	1.00 (0.70‒1.00)	1.00 (0.90‒1.00)	503.6	0.00	205 953	1.00 (0.99‒1.00)
Reference standard
Pathological examination	4	0.82 (0.69‒0.90)	0.93 (0.60‒0.99)	12.3	0.19	63	0.90 (0.87‒0.93)
Pathological examination in BTC group	16	0.75 (0.52‒0.89)	0.98 (0.94‒0.99)	33.7	0.26	130	0.98 (0.96‒0.99)
Clinical assessment	8	0.87 (0.66‒0.96)	0.95 (0.68‒0.99)	18.2	0.14	129	0.96 (0.94‒0.97)

Subgroup	Study/n	Sensitivity (95%CI)	Specificity (95%CI)	PLR	NLR	DOR	AUC (95%CI)
Overall	28	0.80 (0.67‒0.88)	0.96 (0.92‒0.98)	22.7	0.21	108	0.96 (0.94‒0.98)
Study type
Prospective study	16	0.74 (0.51‒0.89)	0.97 (0.93‒0.99)	26.1	0.26	99	0.97 (0.95‒0.98)
Retrospective study	10	0.86 (0.72‒0.93)	0.93 (0.73‒0.99)	12.4	0.15	81	0.95 (0.92‒0.96)
Sample size
>90	12	0.89 (0.78‒0.95)	0.96 (0.83‒0.99)	20.9	0.12	179	0.96 (0.94‒0.98)
≤90	16	0.67 (0.47‒0.83)	0.97 (0.92‒0.99)	23.9	0.34	71	0.96 (0.94‒0.97)
Method
Gene or mutation analysis	6	0.67 (0.44‒0.84)	1.00 (0.85‒1.00)	457.0	0.33	1 394	0.95 (0.93‒0.97)
qPCR	13	0.94 (0.84‒0.98)	0.98 (0.88‒1.00)	38.8	0.06	644	0.99 (0.98‒1.00)
Methylation analysis	9	0.51 (0.37‒0.65)	0.94 (0.82‒0.98)	9.2	0.52	18	0.77 (0.73‒0.81)
Sample type
Bile	4	0.70 (0.53‒0.83)	1.00 (0.67‒1.00)	511.0	0.30	1 690	0.95 (0.92‒0.96)
Serum	19	0.85 (0.66‒0.94)	0.97 (0.90‒0.99)	24.7	0.16	156	0.97 (0.96‒0.99)
Plasma	5	0.72 (0.45‒0.89)	0.92 (0.70‒0.98)	9.4	0.30	31	0.91 (0.88‒0.93)
Control type
Benign biliary disease	18	0.68 (0.54‒0.79)	0.96 (0.92‒0.99)	19.0	0.34	57	0.93 (0.91‒0.95)
Healthy population	6	1.00 (0.70‒1.00)	1.00 (0.90‒1.00)	503.6	0.00	205 953	1.00 (0.99‒1.00)
Reference standard
Pathological examination	4	0.82 (0.69‒0.90)	0.93 (0.60‒0.99)	12.3	0.19	63	0.90 (0.87‒0.93)
Pathological examination in BTC group	16	0.75 (0.52‒0.89)	0.98 (0.94‒0.99)	33.7	0.26	130	0.98 (0.96‒0.99)
Clinical assessment	8	0.87 (0.66‒0.96)	0.95 (0.68‒0.99)	18.2	0.14	129	0.96 (0.94‒0.97)

[1]	CHEN Hui, ZHU Weiyi, YAO Yijin. A meta-analysis of the effects of levothyroxine dose adjustment on maternal and infant outcomes in pregnant women with hypothyroidism [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(7): 906-915.
[2]	WANG Yingwen, LI Xiaoling, DAI Jiajia, LIU Fang, HUANG Jianfeng, WANG Libo, ZHANG Xiaobo, FENG Rui. Epidemiological characteristics and risk factors of severe asthma in children: a single-center prospective cohort study [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(6): 665-672.
[3]	DANG Xiangyang, TANG Yuyi, LI Weiguo, LIU Enmei. Diagnostic value of fractional exhaled nitric oxide in predicting cough variant asthma in children with chronic cough: a systematic review and meta-analysis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(6): 680-688.
[4]	LI Ying, TAN Yangxia, YIN Hongxin, JIANG Yanling, CHEN Li, MENG Guoyu. Research progress in the pathogenesis and prognosis of ZNF384 fusion subtype acute leukemia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(5): 631-640.
[5]	MA Zhuoran, YUAN Ancai, JIANG Huiru, CHEN Xiaoyu, ZHANG Wei, PU Jun. Meta analysis of correlation between lipid accumulation product and hypertension in Chinese adults [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(4): 466-473.
[6]	FENG Jiali, PENG Yu, DUAN Junkai. Progress in functional mechanisms and biomarkers of miRNA related to Kawasaki disease [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(2): 256-260.
[7]	HOU Shumin, SHAO Jingbo. Research progress in clinical characteristics, diagnosis and prognosis of TdT-negative lymphoblastic lymphoma/acute lymphoblastic leukemia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 120-124.
[8]	YANG Ling, HOU Lili, ZHAO Yan, CHEN Weihong, ZHANG Jinfeng, MAO Yan. A meta-analysis of prevalence of mouth opening restriction in patients with oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 61-69.
[9]	FANG Fang, TAI Rui, YU Qian, ZHANG Yaqing. Effect of prehabilitation on outcomes in patients undergoing elective gastrointestinal surgery: a systematic review [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 70-78.
[10]	HE Dongmei, YANG Chi. Diagnosis and treatment protocol of mandibular condylar fracture: experience from the TMJ Center of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(6): 695-701.
[11]	HE Dongmei, YANG Chi. Diagnosis and treatment protocol of temporomandibular joint (TMJ) ankylosis: experience from the TMJ Center of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(6): 702-708.
[12]	ZHANG Shanyong, YANG Chi. Protocols for diagnosis and treatment of temporomandibular joint osteoarthritis: experience from the TMJ Center of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(6): 709-716.
[13]	LÜ Yongfen, LI Pin. Molecular diagnosis and clinical significance of 21-hydroxylase deficiency [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 557-561.
[14]	CHEN Weihong, HOU Lili, YANG Ling, MAO Yan, ZHANG Jinfeng. Efficacy of preventive intervention of cryotherapy on radiation-induced oral mucositis in head and neck cancer: a meta-analysis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 635-645.
[15]	Yingchao TAN, Junyue YANG, Lina WANG. Association between interleukin-1B-511C/T gene polymorphism and coronary atherosclerotic heart disease: a meta-analysis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(2): 197-204.