MicroRNAs as diagnostic and prognostic biomarkers in chemotherapy-induced peripheral neuropathy: A systematic review

Table 1 Summary of the main characteristics of the studies selected in the systematic review, mean ± SD/median (range)/n (%)

Ref.	Design	Country	Malignancy type	Number of participants	Age (years)	Gender	Antineoplastic agents	CIPN diagnosis	CIPN/non-CIPN	Sample	miRNAs detection
Davey et al[36], 2023	Prospective cohort	Ireland	Breast cancer	101	55 (25-76)	M: 0 (0%); F: 101 (100%)	Paclitaxel. AC-T (n = 56) TC-H (n = 19) TC-HL (n = 6) other (n = 20)	NCI-CTCAE	34/67	Whole blood	qRT-PCR
Ju et al[37], 2022	Prospective cohort	South Korea	Gastric cancer	32	55.6 ± 11.5	M: 25 (78.1); F: 7 (21.9)	Oxaliplatin (XELOX)	NCI-CTCAE	18/14	Plasma	qRT-PCR
Ju et al[38], 2024	Prospective cohort	South Korea	Colorectal cancer	27	62.4 ± 5.1	M: 14 (51.9); F: 13 (48.1)	Oxaliplatin (FOLFOX)	NCI-CTCAE	15/12	Plasma	qRT-PCR
Łuczkowska et al[39], 2021	Case-control	Poland	Multiple myeloma	60	65.4 ± 8.31	M: 39 (65); F: 21 (35)	Bortezomib. VTD (n = 36) VMP (n = 8) VD (n = 3) VCD (n = 3) VRD (n = 1) RD (n = 10)	NCI-CTCAE	32/28	Plasma	Microarrays technique and qRT-PCR
Noda-Narita et al[40], 2020	Retrospective cohort	Japan	Breast cancer	84	CIPN group: 54 (34-74); non-CIPN group: 46 (27-73)	M: 0 (0); F: 84 (100)	Paclitaxel	NCI-CTCAE	38/46	Plasma	Microarray hybridization

M: Males; F: Females; CIPN: Chemotherapy-induced peripheral neuropathy; miRNA: MicroRNA; AC-T: Doxorubicin and cyclophosphamide followed by paclitaxel; TC-H (L): Docetaxel, carboplatin followed by trastuzumab (and lapatinib); NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; qRT-PCR: Quantitative reverse transcription polymerase chain reaction; XELOX: Oxaliplatin and capecitabine; FOLFOX: 5-fluorouracil, leucovorin, and oxaliplatin; VTD: Bortezomib, thalidomide, dexamethasone; VMP: Bortezomib, melphalan, prednisone; VD: Bortezomib, dexamethasone; VCD: Bortezomib, cyclophosphamide, dexamethasone; VRD: Lenalidomide, bortezomib, dexamethasone; RD: Lenalidomide, dexamethasone.

Table 2 New Castle Ottawa Scale for quality assessment of observational studies

Ref.	Selection				Comparability	Outcome/exposure
	Representative exposed cohort	Selection of non-exposed cohort	Ascertainment of exposure	Outcome of interest not present at baseline	Comparability of cohorts (design, analysis)	Outcome assessment	Was follow-up long enough for outcomes to occur?	Adequacy of follow-up	Quality
Davey et al[36], 2023	★	★	★	★	★	★	★	-	Good
Ju et al[37], 2022	★	★	★	-	★	★	★	★	Good
Ju et al[38], 2024	★	★	★	-	★	★	★	★	Good
Noda-Narita et al[40], 2020	★	-	★	-	★	★	★	★	Good
Case-control studies	Case definition	Representative cases	Control selection	Control definition	Comparability of cases and controls (design, analysis)	Ascertainment of exposure	Ascertainment. Methods for cases and controls	Non-response rate
Łuczkowska et al[39], 2021	★	★	★	★	★	★	★	-	Good

Table 3 Differentially expressed microRNAs associated with chemotherapy-induced peripheral neuropathy and their predicted target genes and biological pathways

Ref.	miRNAs expression	Target genes	Biological pathways
Davey et al[36], 2023	Let-7a: No difference; miR-21: No difference; miR-145: No difference; miR-155: No difference; miR-195: No difference	N/A	N/A
Ju et al[37], 2022	hsa-miR-885-5p: Downregulation; hsa-miR-378f: Downregulation; hsa-miR-200c-3p: Downregulation; hsa-miR-4666a-3p: Downregulation	ACACA, AKT1, MYRF, NDST1, KCNJ6, P4HB, RAP1B, REST, TGFB2, YY1, TXNL1, IGDCC3, WTAP, HIPK3, ZNF609, PRKD2, RDH11, LGSN, CAB39, SPA17, ARL8B, WDR33, RCC2, CELF4, CYP20A1, ESYT2, CACNG8, DCTPP1, HAUS3, VPS37B, LMNB2, PPARGC1B, DPY19 L3, ARGFX	Peptidyl-serine phosphorylation. Regulation of alternative mRNA splicing. Gastric cancer signaling. Neurotrophin signaling. Mitogen-activated protein kinase signaling. Adenosine monophosphate-activated protein kinase signaling
Łuczkowska et al[39], 2021	miRNA191-5p: Upregulation; miRNA23a-3p: Upregulation; miRNA24-3p: Upregulation; miRNA92: Upregulation; miRNA22: Upregulation	NTRK2, NYAP2, ERBB3, SNAP91, ERBB4, GLDN, NFIB, HIPK1, WNT1, CDX2, CEBPD, TP53INP1, ESR1, EYA3, EZH1, PER1, MECOM	Neuron apoptotic process. Neuron apoptosis. Neuronal stem cell maintenance. Neural tube closure. Regulation of intrinsic apoptotic signaling. Regulation of extrinsic apoptotic signaling. Apoptotic mitochondrial changes
Noda-Narita et al[40], 2020	miR-451a: No difference; miR-6849-5p: No difference; miR-1290: No difference; miR-4476: No difference; miR-204-3p: No difference; miR-23a-3p: No difference; miR-6846-5p: No difference; miR-6870-5p: No difference; miR-5008-5p: No difference; miR-1249-5p: No difference; miR-6806-5p: No difference; miR-4718: No difference; miR-619-5p: No difference; miR-4462: No difference; miR-4539: No difference	N/A	N/A

miRNA: MicroRNA; N/A: Not applicable.

Table 4 Qualitative assessment of clinical and methodological heterogeneity across included studies

Ref.	Cancer type	Neurotoxic agent	Study design	CIPN definition/grading	Sample source	miRNA platform	Timing of sampling	Key source of heterogeneity
Davey et al[36], 2023	Breast cancer	Paclitaxel	Prospective cohort	NCI-CTCAE (grade not stratified)	Whole blood	qRT-PCR (predefined panel)	During chemotherapy	Whole blood vs plasma/serum; limited miRNA panel
Ju et al[37], 2022	Gastric cancer	Oxaliplatin (XELOX)	Prospective cohort	NCI-CTCAE; cycle-based severity	Plasma	Small RNA sequencing + qRT-PCR validation	After < 4 vs ≥ 4 cycles	Cycle-based CIPN definition; sequencing-based discovery
Ju et al[38], 2024	Colorectal cancer	Oxaliplatin (FOLFOX)	Prospective cohort	NCI-CTCAE; ≤ 3 vs ≥ 6 cycles	Plasma	RNA sequencing + qRT-PCR validation	Early vs late chemotherapy exposure	Dose/cycle-based stratification; stress biomarker integration
Łuczkowska et al[39], 2021	Multiple myeloma	Bortezomib-based regimens	Case-control	NCI-CTCAE (IMWG-adapted)	Plasma	Microarray + qRT-PCR validation	During treatment	Different malignancy and neurotoxicity mechanism
Noda-Narita et al[40], 2020	Breast cancer	Paclitaxel	Retrospective cohort	NCI-CTCAE ≥ grade 2 vs ≤ 1	Serum	Microarray	Pre-treatment	Different grade threshold and retrospective design

CIPN: Chemotherapy-induced peripheral neuropathy; miRNA: MicroRNA; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; RNA sequencing: RNA sequencing (typically small RNA sequencing when profiling miRNAs); qRT-PCR: Quantitative reverse transcription polymerase chain reaction; XELOX: Oxaliplatin and capecitabine; FOLFOX: 5-fluorouracil, leucovorin, and oxaliplatin; IMWG: International Myeloma Working Group.