. 2023 Dec 10;96(1):250–280. doi: 10.1111/prd.12542

TABLE 1.

Nucleic acid‐based biomarkers of OSCC.

Author/Year	Sources of biomarkers	Type of markers	Method	Sample size	Potential Biomarkers	Expression in OSCC
Genomic biomarkers for HPV‐positive OSCC
Campo et al. ¹⁵⁷	Plasma	HPV cfDNA	Systematic review and Meta‐analysis	457	cfHPV DNA	Increased in OSCC compared to control
Tang et al. ¹⁵⁸	Saliva	HPV DNA	Nested PCR	650	HPV16	Increased in OSCC compared to control
Rosenthal et al. ²⁹	Saliva	HPV DNA	qPCR and Cobas® HPV Test	45	fHPV16, p16INK4a	Increased in OSCC compared to control
Rettig et al. ¹⁵⁹	Plasma	HPV ctDNA	Droplet Digital PCR	110	ctHPV DNA16, 18, 31, 33, and 35	Increased in OSCC compared to control
Cao et al. ¹⁶⁰	Plasma	HPV ctDNA	Droplet Digital PCR	34	HPV ctDNA	Increased in OSCC compared to control
Haring et al. ¹⁶¹	Plasma	HPV ctDNA	Droplet Digital PCR	12	ctHPV16 DNA	Increased in OSCC compared to control
Veyer et al. ¹⁶²	Plasma	HPV ctDNA	Droplet Digital PCR	66	ctHPV16 DNA	Increased in OSCC compared to control
Reder et al. ¹⁶³	Plasma	HPV cfDNA	qPCR	50	HPV oncogenes E6 and E7	Increased in OSCC compared to control
Mazurek et al. ³⁰	Plasma	HPV cfDNA	qPCR	263	cfHPV‐DNA	Increased in OSCC compared to control
Chera et al. ¹⁶⁴	Plasma	HPV ctDNA	Digital droplet PCR	218	ctHPV16 DNA	Increased in OSCC compared to control
Lee et al. ¹⁶⁵	Plasma	HPV ctDNA	RT‐qPCR	55	ctHPV16 DNA	Increased in OSCC compared to control
Simoens et al. ¹⁶⁶	Tissue	HPV DNA	RT‐PCR	99	E6/E7 + P16(INK4a)	30.9% prevalence in OSCC
Gillison et al. ³¹	Tissue	Gene Mutations	Whole genome sequencing	484	PIK3CA, ZNF750, FGFR3, CASZ1, PTEN, CYLD, and DDX3X	Increased gene mutation frequency in HPV‐positive OSCC, compared to HPV‐negative OSCC
Gillison et al. ³¹	Tissue	Gene Mutations	Whole genome sequencing	484	TP53, FAT1, CDKN2A, NOTCH1, CASP8, and HRAS	Increased gene mutation frequency in HPV‐negative OSCC, compared to HPV‐positive OSCC
Genomic biomarkers for HPV‐negative OSCC
Yang et al. ¹⁶⁷	Saliva	ctDNA mutations	Review article	274	TP53, CDKN2A, PIK3CA, FAT1, and NOTCH1	Increased in OSCC compared to control
Puttipanyalears et al. ¹⁶⁸	Saliva	Gene methylation	RT‐PCR	24	Thyroid Releasing Hormone gene cg01009664	Increased in OSCC compared to control
D'Cruz et al. ¹⁶⁹	Oral Rinse	Gene mutations	PCR	15	TP53	Two identified mutations; 67% of the patients had codon 72 polymorphisms
Shanmugam et al. ¹⁷⁰	Oral Rinse	Gene expression	Digital Droplet PCR	121	TP53, CDKN2A, FAT1, CASP8, NOTCH1, HRAS and PIK3CA	87.6% of the samples presented at least 1 mutation on the genes
Wise‐Draper et al. ³³	Plasma	Gene expression	ELISA	36	DEK	Decreased in poor prognosis compared to control
Schneider et al. ¹⁷¹	Tissue	Gene expression	TCGA Database Analysis	499	GRP78/BiP	Increased gene expression in OSCC compared to control and associated with poor patient survival
Sato et al. ¹⁷²	Tissue	Protein expression	Immunohistochemistry	32	Casein kinase 1ε (cK‐1ε) and CD44	Downregulated in OSCC compared to control
Sato et al. ¹⁷²	Tissue	Protein expression	Immunohistochemistry	32	Differentiated embryonic chondrocyte gene 1 (DEC1)	Upregulated in OSCC compared to control
Wilde et al. ¹⁷³	Tissue	Protein expression	Immunohistochemistry	297	p16	Increased in OSCC compared to control
Shieu et al. ¹⁷⁴	Tissue	Single‐Nucleotide Polymorphisms	RT‐qPCR	568	Lysine methyltransferase 2C (KMT2C) SNPs rs4725443 and rs6943984	TC or TC + CC genotype of rs4725443 > TT genotype.
Shi et al. ¹⁷⁵	Tissue	Gene expression	TCGA and GEO databases	520	SEC61G	Increased in OSCC compared to control
Rapado‐González et al. ¹⁷⁶	Tissues, blood and saliva	cfDNA	qPCR	34	ALU60	Increased in OSCC patients compared to control, but not statistically significant
Burcher et al. ¹⁷⁷	Tissue/Blood	DNA Damage Repair gene mutation	ELISA	170	BRCA1, BRCA2, ATM, PALB2, ARID1A and CDK12	Increased in OSCC compared to control
Shi et al. ³²	Cell line derived from an oral cancer‐induced mouse model	Gene Mutation	Whole‐exome sequencing (WES),	N/A	TP53, Fat1, Notch1, Kmt2d, Fat3, and Fat4	TP53 mutations have 75%–85% prevalence in OSCC
Arora et al. ¹⁷⁸	Databases and in vitro	Gene expression	Bioinformatics	545	TFRC and NCBP2	Increased in OSCC compared to control; NCBP2 depletion reduced OSCC cell proliferation, migration, and invasion
Yang et al. ¹⁷⁹	Databases	Gene dysregulation	Bioinformatics	335	SPP1, FN1, CXCL8, BIRC5, PLAUR, and AURKA	Upregulated in OSCC compared to Control
Yang et al. ¹⁷⁹	Databases	Gene dysregulation	Bioinformatics	335	TEX101, DSG2, SCG5, ADA, BOC, SCARA5, FST, SOCS1, and STC2	Can be utilized to predict prognosis of OSCC patients
Transcriptomic biomarkers
Dioguardi et al. ¹⁸⁰	Tissue	MicroRNAs	Systematic review and Meta analysis	708	miR‐21	Upregulated in OSCC compared to control; Aggregated Hazard Ratio 1.29
Xie & Wu ¹⁸¹	Tissue	MicroRNA	Systematic Review and Meta analysis	777	miR‐21	Upregulated in OSCC compared to control; Aggregated Hazard Ratio 1.93;
Niklander et al. ¹⁸²	Tissue, In vivo and In vitro	MicroRNAs	Systematic Review	N/D	miR‐21, mir‐146a, miR‐181b, miR‐184, miR‐345	Increased in OSCC compared to control and oncogenic
Niklander et al. ¹⁸²	Tissue, In vivo and In vitro	MicroRNAs	Systematic Review	N/D	miR‐375	Downregulated and tumor suppressor
Palaia et al. ³⁴	N/D	MicroRNA	Systematic Review	3102	miR‐16‐let‐7b, miR‐21, miR‐24, miR‐24‐3p, miR‐27a‐3p, miR‐27b, miR‐31, miR‐92b, miR‐136, miR‐147, miR‐148a, miR‐150‐5p, miR‐155, miR‐181a, miR181b, miR‐184, miR‐187, miR‐191, miR‐196a, miR‐196b, miR‐200b‐2p, miR‐210, miR‐220a, miR‐223, miR‐323‐5p, miR‐412‐3p, miR‐423‐5p, miR‐483‐5p, miR‐494, miR‐503, miR‐512‐3p, miR‐626, miR‐632, miR‐646, miR‐668, miR‐887, miR‐1250, miR‐3262, miR‐3651, miR‐5100	Upregulated in OSCC compared to control
Palaia et al. ³⁴	N/D	MicroRNA	Systematic Review	3102	miR‐let‐7d, miR‐9, miR‐29a, miR‐30a‐5p, miR‐99a, miR‐125a, miR‐139‐5p, miR‐145, miR‐186, mir‐200a, miR‐223, miR‐223‐3p, miR‐320a, miR‐338‐3p, miR‐758, miR‐769‐5p	Downregulated in OSCC compared to control
Troiano et al. ¹⁸³	Blood, Serum, and Plasma	MicroRNA	Systematic Review	1586	miR‐21, miR‐455‐5p, miR‐155‐5p, miR‐372, miR‐373, miR‐29b, miR‐1246, miR‐196a, and miR‐181	Upregulated in OSCC compared to control
Troiano et al. ¹⁸³	Blood, Serum, and Plasma	MicroRNA	Systematic Review	1586	miR‐204, miR‐101, miR‐32, miR‐20a, miR‐16, miR‐17, and miR‐125b	Downregulated in OSCC compared to control
Scholtz et al. ³⁶	Saliva	MicroRNAs	RT‐qPCR	87	miR‐345 miR‐31‐5p, and miR‐424‐3p miR‐21 miR‐184 miR‐191	Upregulated in OSCC compared to control
Shen et al. ¹⁸⁴	Tissue	MicroRNA	RT‐qPCR	70 for miR and 50 for target genes	miR‐21‐5p	Upregulated in OSCC compared to control
Shen et al. ¹⁸⁴	Tissue	MicroRNA	RT‐qPCR	70 for miR and 50 for target genes	ADH7 gene	Downregulated in OSCC compared to control
Robison et al. ¹⁸⁵	Tissue	MicroRNAs	RT‐qPCR	16	miR‐155, miR‐196a, miR‐375, and miR‐221	Upregulated in OSCC compared to control; Gender bias toward lymphatic invasion in lesions presenting around the perineal and abdominal regions
Shan et al. ¹⁸⁶	Tissue	Long Noncoding RNA	RT‐PCR	368	M6A‐related lncRNAs HMOX1, NFE2L2, NOS2, NOS3, and TP53	Downregulated in OSCC compared to control; Oxidative Stress in Oral Cancer
Rajthala et al. ¹⁸⁷	Tissue and OSCC‐derived cancer‐associated fibroblasts	MicroRNAs	In Situ Hybridization and miRNA Semi‐Quantification.	50 tissues +18 OSCC‐derived cancer‐associated fibroblasts	miR‐138	Downregulated in OSCC compared to control
Qin et al ¹⁸⁸	Tissue and In vitro	MicroRNAs	RT‐qPCR and Western blot.	60 tissues +6 cell lines	miR‐32‐5p	Upregulated in OSCC compared to control
Jia et al. (2021) ³⁷	Tissue, In vivo PDX and In vitro	Circulating RNA	RT‐qPCR	100	circFAT1, circ_0000231, circ_0001742, circ_0000264, circ_0002837, circ_0007976	Increased in OSCC compared to Control. CircFAT1 promotes cancer stemness and immune evasion by promoting STAT3 activation.
Extracellular Vesicles‐Omics
Saito et al. ¹⁸⁹	N/A	Oncogene	Review	N/A	NANOG and SOX	Increased in OSCC compared to control
Benecke et al. ³⁹	Plasma	Extracellular vesicles markers	Flow Cytometry	21	CD9, CD63, CD81 and TSG101	Increased in OSCC compared to control
Zhuang et al. ⁴⁰	In vitro and In vivo	Exosomal MicroRNAs	Exosomal miRNAs sequencing	N/A	miR‐1246 and miR‐205	Upregulated in OSCC compared to control
Wu et al. ⁴¹	In vitro and In vivo	MicroRNAs	RT‐qPCR	N/A	Cancer stem cell small extracellular vesicles, M2‐tumor‐associated macrophages	Increased in OSCC compared to control
Cancer Stem Cells and Circulating Tumor Cell markers
Fukumoto et al. ²⁴	N/A	Cancer Stem Cells	Review	N/A	OCT4, NANOG, and SOX2	No specific markers for OSCC CSC other than those of general embryonic stem cells
Varun et al. ⁴⁵	N/A	Cancer Stem Cells	Review	N/A	OCT4, SOX2, NANOG, ALDH1, CD44, CD24, CD133 and Musashi‐1	Display CSC characteristics
Rodini et al. ⁴²	N/A	Cancer Stem Cells	Review	N/A	CD44 and ALDH1	Display CSC characteristics; Majority of OSCC CSC isolations performed with CD44 marker
Baillie et al. ¹⁹⁰	N/A	Cancer Stem Cells	Review	N/A	OCT4, NANOG, SOX2, STAT3, CD44, CD24, CD133, Musashi‐1, ALDH1, PRR, ATR1 and ATR2	Display CSC characteristics
Philouze et al. ¹⁹¹	Tissue	Cancer Stem Cells	Immunohistochemistry	28	CD44, gamma‐H2AX, and p‐ATM	Display CSC characteristics
Ma et al. ⁴⁶	Tissue	Cancer Stem Cells	Magnetic‐activated cell sorting	6	CD133, NANOG, SOX2, ALDH1A1, and OCT4	Display CSC characteristics; CD133 is negatively correlated with OSCC patients' survival
Curtin et al. ⁵⁵	N/A	Circulating Tumor Cells	Systematic review	N/A	N/A	CTCs does not appear to be related to tumor differentiation or size; CTCs may be prognostic for both disease‐free survival and overall survival
Qayyumi et al. ⁵²	Blood	Circulating Tumor Cells	Immuno‐magnetic beads separation	192	N/A	Progressively increased counts of CTC cells as OSCC progresses from stage I to IV. CTC detection Sensitivity ‐ 94.32%, CTC detection specificity ‐ 98%, and CTC detection accuracy ‐ 95.17%
Wang et al. ¹⁹²	Blood	Circulating Tumor Cells	Flow cytometry	53	N/A	CTC counts were significantly reduced within 2–4 weeks of chemoradiation
Morgan et al. ⁵³	Blood	Circulating Tumor Cells	Surface‐enhanced Raman scattering nanoparticle‐based separation	125	N/A	Higher CTC counts associated with survival. CTC count of 675 defined as threshold between OSCC recurrence and distant disease, with sensitivity of 69%, and specificity of 68%.
Chang et al. ⁵⁴	Blood	Circulating Tumor Cells and circulating Cancer Stem Cells	Flow cytometry	34	N/A	Overall survival associated with higher CTC counts; Higher CSC ratio predicted disease progression within the first 3 months of chemotherapy.
Fanelli et al. ¹⁹³	Blood	Circulating Tumor Cells	Filtration and immunocytochemistry	53	TGF‐β Receptor I	Expression correlated with poor progression‐free survival