Programmed death 1, ligand 1 and 2 correlated genes and their association with mutation, immune infiltration and clinical outcomes of hepatocellular carcinoma

Table 1 Co-mutation analysis for programmed death 1/programmed death ligand 1/programmed death ligand 2

Gene	Mutation	PD-1 (mean ± SD)	PD-1 P value	PD-L1 (mean ± SD)	PD-L1 P value	PD-L2 (mean ± SD)	PD-L2 P value
ABCA13	NO	0.38 ± 1.47		0.14 ± 0.54		0.34 ± 3.31
	Yes	0.3 ± 0.69	0.675	0.1 ± 0.21	0.431	0.08 ± 0.1	0.705
ALB	NO	0.38 ± 1.46		0.14 ± 0.53		0.33 ± 3.26
	Yes	0.11 ± 0.23	0.242	0.12 ± 0.27	0.545	0.11 ± 0.27	0.121
APOB	NO	0.39 ± 1.46		0.14 ± 0.53		0.34 ± 3.27
	Yes	0.04 ± 0.05	0.102	0.05 ± 0.03	0.858	0.05 ± 0.04	0.835
ARID1A	NO	0.37 ± 1.43		0.14 ± 0.52		0.33 ± 3.22
	Yes	0.59 ± 1.03	0.316	0.1 ± 0.14	0.699	0.13 ± 0.17	0.495
AXIN1	NO	0.37 ± 1.43		0.14 ± 0.52		0.32 ± 3.2
	Yes	0.16 ± 0.08	0.206	0.06 ± 0.02	0.418	0.03 ± 0	0.741
CACNA1E	NO	0.39 ± 1.48		0.14 ± 0.53		0.34 ± 3.32
	Yes	0.13 ± 0.44	0.046	0.09 ± 0.26	0.083	0.07 ± 0.17	0.076
CSMD3	NO	0.35 ± 1.42		0.14 ± 0.53		0.34 ± 3.29
	Yes	0.67 ± 1.49	0.286	0.07 ± 0.09	0.981	0.12 ± 0.14	0.633
CTNNB1	NO	0.43 ± 1.61		0.17 ± 0.6		0.42 ± 3.75
	Yes	0.22 ± 0.75	0.02	0.06 ± 0.1	0.428	0.07 ± 0.09	0.554
FLG	NO	0.39 ± 1.48		0.1 ± 0.27		0.13 ± 0.55
	Yes	0.22 ± 0.52	0.78	0.49 ± 1.53	0.893	2.34 ± 10.8	0.204
LRP1B	NO	0.39 ± 1.48		0.14 ± 0.54		0.34 ± 3.32
	Yes	0.2 ± 0.41	0.519	0.1 ± 0.17	0.554	0.12 ± 0.3	0.886
MUC16	NO	0.32 ± 1.31		0.14 ± 0.55		0.35 ± 3.47
	Yes	0.64 ± 1.93	0.697	0.13 ± 0.3	0.521	0.18 ± 0.53	0.997
MUC4	NO	0.38 ± 1.44		0.14 ± 0.52		0.33 ± 3.23
	Yes	0.13 ± 0.3	0.196	0.1 ± 0.11	0.641	0.08 ± 0.1	0.753
OBSCN	NO	0.4 ± 1.49		0.1 ± 0.27		0.14 ± 0.55
	Yes	0.15 ± 0.42	0.267	0.46 ± 1.46	0.087	2.13 ± 10.37	0.518
PCLO	NO	0.33 ± 1.3		0.14 ± 0.54		0.35 ± 3.36
	Yes	0.75 ± 2.29	0.712	0.1 ± 0.22	0.422	0.1 ± 0.17	0.974
RYR1	NO	0.34 ± 1.29		0.14 ± 0.54		0.34 ± 3.31
	Yes	0.74 ± 2.59	0.101	0.05 ± 0.04	0.872	0.06 ± 0.05	0.705
RYR2	NO	0.36 ± 1.41		0.13 ± 0.5		0.34 ± 3.34
	Yes	0.47 ± 1.58	0.03	0.24 ± 0.67	0.113	0.12 ± 0.2	0.321
SPTA1	NO	0.39 ± 1.48		0.14 ± 0.54		0.33 ± 3.31
	Yes	0.18 ± 0.4	0.737	0.1 ± 0.21	0.201	0.15 ± 0.36	0.384
TP53	NO	0.3 ± 1.22		0.08 ± 0.18		0.1 ± 0.28
	Yes	0.65 ± 2.04	0.016	0.35 ± 1.08	0.003	1.19 ± 7.04	0.041
TTN	NO	0.45 ± 1.62		0.15 ± 0.59		0.4 ± 3.66
	Yes	0.14 ± 0.38	0.014	0.08 ± 0.18	0.291	0.08 ± 0.2	0.028
XIRP2	NO	0.31 ± 1.12		0.13 ± 0.51		0.31 ± 3.31
	Yes	1.02 ± 3.15	0.26	0.19 ± 0.63	0.235	0.39 ± 1.54	0.329

PD-1: Programmed death 1; PD-L1: Programmed death ligand 1; PD-L2: Programmed death ligand 2; SD: Standard deviation.

Table 2 GO analysis for programmed death 1/programmed death ligand 1/programmed death ligand 2 co-expression gene

ID	Description	Gene ratio	P value	P adjust	Gene ID	Count
GO: 0042110	T cell activation	16/27	1.23 × 10-19	1.10 × 10-16	PTPN6/CD3E/LCK/PDCD1/CD3G/IDO1/TNFRSF4/TIGIT/PTPRC/CD40LG/PRDM1/EOMES/CD2/CD5/CD8A/IRF4	16
GO: 0050863	Regulation of T cell activation	12/27	4.55 × 10-15	2.05 × 10-12	PTPN6/CD3E/LCK/PDCD1/IDO1/TIGIT/PTPRC/CD40LG/PRDM1/CD2/CD5/IRF4	12
GO: 0051249	Regulation of lymphocyte activation	13/27	2.40 × 10-14	5.40 × 10-12	PTPN6/CD3E/LCK/PDCD1/IDO1/TNFRSF4/TIGIT/PTPRC/CD40LG/PRDM1/CD2/CD5/IRF4	13
GO: 1903037	Regulation of leukocyte cell-cell adhesion	10/27	5.69 × 10-12	1.02 × 10-9	PTPN6/CD3E/LCK/PDCD1/IDO1/TIGIT/PTPRC/CD40LG/CD5/ITGA4	10
GO: 0007159	Leukocyte cell-cell adhesion	10/27	1.68 × 10-11	2.53 × 10-9	PTPN6/CD3E/LCK/PDCD1/IDO1/TIGIT/PTPRC/CD40LG/CD5/ITGA4	10
GO: 0007204	Positive regulation of cytosolic calcium ion concentration	9/27	3.25 × 10-10	2.66 × 10-8	PTPN6/LCK/CD19/PTPRC/CXCR3/FASLG/CXCR4/CD52/CXCL9	9
GO: 0050852	T cell receptor signaling pathway	9/27	1.56 × 10-9	1.00 × 10-7	PTPN6/CD3E/LCK/HLA-DQB1/CD3G/PTPRC/CD247	7
GO: 0055074	Calcium ion homeostasis	9/27	1.08 × 10-8	4.87 × 10-7	PTPN6/LCK/CD19/PTPRC/CXCR3/FASLG/CXCR4/CD52/CXCL9	9
GO: 0051209	Release of sequestered calcium ion into cytosol	6/27	1.42 × 10-8	5.81 × 10-7	PTPN6/LCK/CD19/PTPRC/FASLG/CXCL9	6
GO: 0006968	Cellular defense response	5/27	2.52 × 10-8	8.11 × 10-7	TNFRSF4/CD19/PRF1/CXCL9/SH2D1A	5
GO: 0050867	Positive regulation of cell activation	5/8	2.00 × 10-7	5.23 × 10-5	PDCD1LG2/JAK2/CD274/ITPKB/PDGFRB	5
GO: 0022407	Regulation of cell-cell adhesion	5/8	2.11 × 10-7	5.23 × 10-5	PDCD1LG2/JAK2/CD44/CD274/ITPKB	5
GO: 0045785	Positive regulation of cell adhesion	5/8	2.36 × 10-7	5.23 × 10-5	PDCD1LG2/JAK2/CD44/CD274/ITPKB	5
GO: 0060333	Interferon-gamma-mediated signaling pathway	3/8	6.13 × 10-6	0.000528087	JAK2/CD44/NCAM1	3
GO: 0007159	Leukocyte cell-cell adhesion	4/8	6.35 × 10-6	0.000528087	PDCD1LG2/CD44/CD274/ITPKB	4
GO: 2001269	Positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway	2/8	7.36 × 10-6	0.000543547	JAK2/FAS	2
GO: 0046007	Negative regulation of activated T cell proliferation	2/8	8.99 × 10-6	0.000597772	PDCD1LG2/CD274	2
GO: 0032693	Negative regulation of interleukin-10 production	2/8	2.22 × 10-5	0.001230174	PDCD1LG2/CD274	2
GO: 0032516	Positive regulation of phosphoprotein phosphatase activity	2/8	3.42 × 10-5	0.001626763	JAK2/PDGFRB	2
GO: 0055093	Response to hyperoxia	2/8	3.42 × 10-5	0.001626763	FAS/PDGFRB	2

P < 0.05 was considered significant.

Table 3 Correlation analysis for immune checkpoints and programmed death 1/programmed death ligand 1/programmed death ligand 2

	PD-1 r	PD-1 padj	PD-L1 r	PD-L1 padj	PD-L2 r	PD-L2 padj
CD28	0.57465488	4.28 × 10-34	0.6660232	9.08 × 10-49	0.71414661	6.86 × 10-59
CD80	0.63623359	1.59 × 10-43	0.67510422	2.19 × 10-50	0.70070417	4.16 × 10-56
CD86	0.72311298	2.38 × 10-61	0.69521618	2.70 × 10-54	0.79715204	1.59 × 10-82
CTLA4	0.82827652	6.53 × 10-95	0.53400839	9.77 × 10-29	0.62325084	2.09 × 10-41
RGMB	0.08079832	0.11878686	0.31356282	5.62 × 10-10	0.15655839	0.00239497
CD58	0.4020193	6.49 × 10-16	0.44699953	1.00 × 10-19	0.34510312	7.46 × 10-12
CD27	0.8554091	2.51 × 10-107	0.564041	1.70 × 10-32	0.70361681	1.23 × 10-56
CD70	0.73757481	6.84 × 10-65	0.49791513	1.14 × 10-24	0.5810653	5.35 × 10-35
HLA-A	0.49005962	6.82 × 10-24	0.45628329	1.56 × 10-20	0.47535158	2.20 × 10-22
CD74	0.62377393	1.71 × 10-41	0.57693716	3.59 × 10-34	0.68544635	6.61 × 10-53

PD-1: Programmed death 1; PD-L1: Programmed death ligand 1; PD-L2: Programmed death ligand 2.