Precision medicine for gastrointestinal cancer: Recent progress and future perspective

Table 1 Current progress of circulating tumor cells, circulating tumor DNA and stool DNA as diagnostic, monitoring and predictive markers in gastrointestinal cancer

Liquid biopsy	Patients/ controls	Organs	Source of fluid	Abnormalities	Technology	Target	Clinical setting	Ref.
CTCs	140/0	EC	B		FIHC	CK19, CD45	Prognosis	Li et al[82], 2016
CTCs	NA	EC	B		ISET	NA	Prognosis	Han et al[83], 2019
CTCs	116/31	GC	B		FAST-disc	EpCAM, CK, CD45-	Diagnostic	Kang et al[84], 2017
CTCs	81/31	GC	B		ISET	CK8/18/19, Vimentin, CD45	Prognostic	Zheng et al, 2017
CTCs	101/31	GC	B		CellSearch and IF-FISH	EpCAM, CK8, CK18, CK19, CD45-, HER2	Predictive	Mishima et al[86], 2017
CTCs	121/0	CRC	B		Cyttel method/imFISH	CD45	Prognostic	Wang et al[87], 2019
ctDNA	11/0	EC	P, T, NT	Mutation	WES and NGS panel		Diagnostic /Therapeutic	Luo et al[88], 2016
ctDNA	13/0	EC	P, T	Mutation	NGS panel		Predictive	Ueda et al[89], 2016
ctDNA	63/0	EC	P	Copy number status	qPCR	CCND1	Predictive	Komatsu et al[90], 2014
cfDNA	32/0	GC	P	Copy number status	cfDNA NGS testing	ERBBB2	Therapeutic	Kim et al[91], 2018
ctDNA	277/0	EC/GC	P, T	Mutation	MassARRAY	TP53, PIK3CA, ERBB2, KRAS	Diagnostic /Prognostic	Kato et al, 2018
ctDNA	70/0	GC	P, T	Mutation	NGS panel	HER2	Therapeutic	Gao et al[93], 2017
cfDNA	60/30	GC	P	Mutation	Droplet digital PCR	HER2	Therapeutic	Shoda et al[94], 2017
ctDNA	1/0	GC	P, T	Mutation	NGS panel	MET	Therapeutic	Du et al30], 2017
ctDNA	230/0	CRC	B	Mutation	Safe-SeqS assay	NA	Prognostic	Tie et al[95], 2016
cfDNA	22/0	CRC	S	Mutation	NGS/dPCR	TP53, KRAS, APC, PIK3CA, BRAF, FBXW7, NRAS	Diagnostic /Prognostic	Furuki et al[96], 2018
cfDNA	3/0	CRC	P	Mutation	BEAMing	RAS, BRAF, PIK3CA	Predictive	Klein-Scory et al, 2018
cfDNA	20/0	CRC	P	Mutation	Droplet digital PCR	APC, TP53, KRAS, PI3CA	Predictive	Vandeputte et al[97], 2018
Stool DNA	71/22	CRC	Stool	Methylation	QIAamp DNA Stool Mini Kit	SDC2	Diagnostic	Oh et al[98], 2017

EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; NT: Normal tissue; B: Blood; P: Plasma; S: Serum; T: Tumor tissue; PLF: Peritoneal lavage fluid; NGS: Next-generation sequencing; WES: Whole exome sequencing; FIHC: Fluorescent immunohistochemistry; NA: Not avaibable; EpCAM: Epithelial cell adhesion molecule.

Table 2 Current progress of microRNAs and exosome as diagnostic, monitoring and predictive markers in gastrointestinal cancer

Liquid biopsy	Patients/ controls	Organs	Source of fluid	Abnormalities	Technology	Target	Clinical setting	Ref.
MiRNAs	231/0	EC	Peripheral blood lymphocytes	Polymorphism	SNPShot	KIAA0423 rs1053667, GEMIN3 rs197412	Prognostic	Faluyi et al[99], 2017
MiRNAs	3156/0	EC	S/P	Upregulation/Downregulation	NA	miR-15a, miR-22, miR-31, miR-451, miR-506, miR-613, miR-1297	Diagnostic /Prognostic	Yao et al[100], 2018
MiRNAs	125/0	EC	S/P	Upregulation/Downregulation	RT-PCR	miR-21, miR-223, miR-100, miR-25, miR-375	Diagnostic /Prognostic	Zhang et al[101], 2018
MiRNAs	250/538	GC	Gastric juice	Upregulation	miScript RT kit	miR-421, miR-21, miR-106a, miR-129	Diagnostic	Virgilio et al[102], 2018
MiRNAs	20/20	GC	S	Upregulation	TaqMan OpenArray assays	miR-331 and miR-21	Diagnostic	Sierzega et al[103], 2017
MiRNAs	The miRNA expression profile (GSE29298)	CRC	NA -	Upregulation	NA	miR-198, miR-765, miR-630, miR-371-5p, miR-575, miR-202, miR-513a-5p	Predictive	Zhu et al[104], 2017
MiRNAs	232/0	CRC	S	Upregulation	NA	miR-21, miR-29b, miR-92.	Diagnostic	Carter et al[105], 2017
MiRNAs	61/0	CRC	P	Upregulation	miRVANA PARIS kit	miR-20b, miR-29b, miR-155	Prognosis /Predivtive	Ulivi et al[106], 2018
Exosome	66/20	EC	P	Upregulation	AChE activity	Exosomes	Prognostic	Matsumoto et al[107], 2016
Exosome	30/0	GC	PLF	Upregulation	MiRNA microarray	miR-21, miR-1225-5p	Diagnostic /Therapeutic	Tokuhisa et al[108], 2015
Exosome	232/20	GC	P	Downregula-tion	Taqman microRNA assays	miR-23b	Prediction /Prognostic	Kumata et al[109], 2018
Exosome	227/28	CRC	S	Upregulation/Downregula-tion	qRT-PCR microarray	miR-17, miR-18a, miR-19a, miR-19b, miR20a, miR-92a, hsa-miR-25-106b, hsa-miR-17-92a	Predictive /Prognosis	Matsumura et al[110], 2015
Exosome	108/0	CRC	S	Downregula-tion	The total exosome isolation kit	miR-548c-5p	Prognosis	Peng et al[111], 2018

EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; NT: Normal tissue; B: Blood; P: Plasma; S: Serum; T: Tumor tissue; PLF: Peritoneal lavage fluid; NGS: Next-generation sequencing; WES: Whole exome sequencing; FIHC: Fluorescent immunohistochemistry; NA: Not avaibable.

Table 3 Current progress of multiplex gene panels in gastrointestinal cancer

Organs	Panel tested	Number of genes tested	Number of patients	The type of sample	Companion diagnostic indications	Ref.
EC	HiSeq2000	N/A	144	Tumor tissue DNA	CCND1, CDKN2A, FBXW7, MLL2, EP300, CREBBP, TET2, NOTCH1, NOTCH3, FAT1, YAP1, AJUBA, PIK3CA, EGFR, ERBB2	Sawada et al[44], 2016
EC	Exiqon miRNA qPCR panel	168miRNA	140	Serum miRNA	miR-20b-5p, miR-28-3p, miR-192-5p, miR-223-3p, and miR-296-5p	Huang et al[50], 2017
EC	Ion AmpliSeq Custom DNA Panel	12	27	Tumor tissue/Serum DNA	BRAF, DDR2, ERBB2, HRAS, KEAP1, KRAS, NFE2L2, NRAS, PIK3CA, PTEN, RHOA	Pasternack et al[112], 2018
GC	Illumina HiSeq 2000	38	138	Tumor tissue DNA	RHOA, CDH1, PIK3CA, CTNNB1, APC, ARID1A, KMT2C, KRAS	Kakiuchi et al[42], 2014
GC	Illumina HiSeq 2000	N/A	100	Tumor tissue DNA	ARID1A, CDH1, MUC6, CTNNA2, GLI3, RNF43, RHOA	Wang et al[43], 2014
GC	CANCERPLEX	435	207	Tumor tissue DNA	ARID1A, CDH1, ERBB2, CCNE1, KRAS	Ichikawa et al[41], 2017
GC	Ion-Proton sequencer	50	29	Tumor tissue DNA	APC, CTNNB, KRAS, NPM1, FBXW7 ERBB2, FGFR2, KIT	Yoshida et al[113], 2019
CRC	CANCERPLEX	415	201	Tumor tissue DNA	ERBB2, APC, CDKN2A, NRAS, ATM, BLM, BRCA2, NBN, NRE11A	Nagahashi et al[39], 2016
CRC	IT-PGM seqencing	22	77	Tumor tissue DNA	RAS, PIK3CA, FBXW7, BRAF, SMAD4, MET, FGFR1	Capalbo et al [114], 2019
CRC	OncoAim™ DNA panel	39	648	Tumor tissue DNA	KRAS, APC, PIK3CA, SMAD4, BRAF, FBXW7, NRAS	Wang et al[115], 2018
CRC	MiSeq	207	22	Tumor tissue DNA	KRAS, PIK3CA, FBXW7, PTEN, SMAD4, BRAF, CTNNB1, NRAS	Gao et al[116], 2019
CRC	cfDNA panel	14	101	Plasma cfDNA	AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, APC,	Osumi et al, 2018
CRC	TruSight Cancer Sequencing Panel	42	N/A	Blood ctDNA	MLH1, MSH6, PMS2 APC, SMAD4, TP53, BRIP1, CHEK2, MUTYH, HNF1A, XPC	Seifert et al[117], 2019

TP53 was commonly implicated in all references except 28035762, 30297788 and 30523343 (PMID)[50,112,117]. EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; NGS: Next-generation sequencing; FFPE: Formalin-fixed paraffin-embedded; N/A: Not available; EBV: Epstein-Barr virus; MSI: Microsatellite instability; NGS: Next-generation sequencing.

Table 4 Current progress of biomarkers associated with diagnosis, prognosis, prediction of therapeutic response in gastrointestinal cancer (excluding liquid biopsy)

Market	Tumor type	Alteration	Clinical setting	Ref.
HER2	GC, CRC	Amplification, Overexpression	Predictive	Bang et al[118], 2010; Sartore-Bianchi et al[119], 2016
KRAS	CRC	Activating mutation within catalytic RAS domain	Predictive	Wormald et al, 2013; Febbo et al, 2011; Schmoll et al[122], 2012; Locker et al[123], 2006
NRAS,	CRC	Overexpression	Prognostic/Predictive	Hu et al[124], 2018
BRAF	CRC	Mutation	Prognostic/Therapeutic	Tie et al[54], 2011
KDR	CRC	Mutation	Predictive	Loaiza-Bonilla et al[125], 2016
VEGF-D	CRC	Overexpression	Predictive	Tabernero et al[126], 2018
AKT	GC	Activation	Predictive	Ito et al[127], 2017
PTEN	GC	Downregulation	Predictive	Kim et al, 2017
NTRK fusion	CRC	Overexpression	Predictive	Drilon et al[129], 2018
ALK	CRC	Rearrangement	Prognostic	Pietrantonio et al[57], 2017
POLE	CRC	Mutation	Predictive	Domingo et al[130], 2016
MMR	GC, CRC		Predictive	Llosa et al[131], 2015
PD-L1	CRC	Mutatoin	Prognostic	Eriksen et al[132], 2019
Tumor infiltrating lymphocyte	GC, CRC	Overexpression	Prognostic	Iseki et al[133], 2018
CagA	GC	Upregulated	Diagnostic	Saju et al[134], 2016
Gastrokine 1	GC	Downregulated	Diagnostic	Altieri et al[135], 2017
MEK	CRC	Activation	Predictive	Martinelli et al[136], 2017
PIK3CA	CRC	Mutation	Prognostic/ Therapeutic	Jehan et al[137], 2019; Schmoll et al[122], 2012
TP53	EC, GC, CRC	Mutation	Prognostic	Schmoll et al[122], Guo et al[138], 2017
CTNNB1	CRC EC, GC	Mutation Overexpression	Prognostic Prognostic	Gao et al[116], 2019; Szász et al[139], 2016; Ishiguro et al[140], 2016
APC	CRC	Mutation	Prognostic	Liang et al[141], 2017; Chen et al[142], 2013
IGFR-!R	CRC	Upregulation	Prognostic	Codony-Servat et al[143], 2017
SFRP2	CRC	Hypermethylation	Diagnostic/Prognostic	Tang et al, 2011
UGT1A1	CRC	Hypermethylation	Predictive	Crea et al[145], 2011
SMAD4,	EC, GC, CRC	Downregulation	Prognostic/Predictive	Salem et al[146], 2018; Wasserman et al[147], 2019
MET	EC, GC	Amplificatoin	Predictive	Van Cutsem et al[55], 2018
CDKN2A	EC,	Methylation	Diagnostic	Zhou et al, 2017
ATM	GC, CRC	Mutaion/Downregulation	Prognostic	Randon et al[149], 2019; Han et al[83], 2017
BLM,	CRC	Mutaion/Polymorphisms	Diagnostic	de Voer et al[150], 2015; Frank et al[151], 2010
BRCA1/2,	CRC	Mutaion	Diagnostic	Oh et al[152], 2018
ARID1A	GC	Mutation	Predictive	Wei et al[153], 2014
	CRC	Overexpresion	Prognostic	Ronchetti et al[154], 2017
CDH1	GC	Mutation	Diagnostic	Hansford et al[155], 2015
	CRC	Polymorphism	Diagnostic	Grünhage et al[156], 2008
CCNE1	GC	Amplification	Therapeutic	Ooi et al[157], 2017
RHOA	GC, CRC	Overexpression	Prognostic	Chang et al[158], 2016
CCND1	EC	Amplification/Overexpression	Diagnostic	Hu et al[159], 2016
	CRC	Polymorphism	Diagnostic	Grünhage et al[156], 2008
FBXW7	CRC	Mutation	Prognostic	Korphaisarn et al[160], 2017
NOTCH1	EC	Mutation	Prognostic	Song et al[161], 2016
	CRC	Gene copy number	Prognostic	Arcaroli et al[162], 2016
NOTCH3	CRC	Overexpression	Predictive	Ozawa et al[163], 2014
YAP1	EC, GC, CRC	Overexpression	Prognostic	Zhang et al[164], 2018

EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; MMR: mismatch repair; PD-L1: programmed death ligand 1; PD-1: programmed death-1; POLE: DNA polymerase 1; HER2: human epidermal growth factor receptor type2; EGFR: epidermal growth factor receptor.