Upregulation of Cartilage Oligomeric Matrix Protein Predicts Poor Prognosis in Urothelial Carcinoma

Figures & data

Table 1 Differential Expression of Genes Associated with the Regulation of Extracellular Matrix Structural Constituent (GO:0005201) in the Transcriptome of Urothelial Carcinoma of the Urinary Bladder (GSE31684) in Connection to Cancer Invasiveness and Metastases

Probe	Comparing MIBC vs NMIBC		Comparing Meta. vs Non-Meta		Gene Symbol	Gene Title	Biological Process
	Log Ratio	p-value
203886_s_at	0.8918	0.0003	0.6266	0.0009	FBLN2	Fibulin 2	Calcium ion binding, extracellular matrix structural constituent, protein binding
204163_at	1.1047	0.0001	0.6313	0.0001	EMILIN1	Elastin microfibril interfacer 1	Extracellular matrix constituent conferring elasticity, extracellular matrix structural constituent, identical protein binding, protein binding
205648_at	0.6169	0.0014	0.4056	0.0061	WNT2	Wingless-type MMTV integration site family member 2	Extracellular matrix structural constituent, signal transducer activity
205713_s_at	1.8386	0.0001	1.1823	0.0001	COMP	Cartilage oligomeric matrix protein	Calcium ion binding, extracellular matrix structural constituent, protein binding
209082_s_at	0.6536	0.0015	0.4516	0.0042	COL18A1	Collagen; type XVIII; alpha 1	Extracellular matrix structural constituent, metal ion binding, protein binding, structural molecule activity, zinc ion binding
209156_s_at	2.1304	0.0001	0.9732	0.0021	COL6A2	Collagen; type VI; alpha 2	Extracellular matrix structural constituent, protein binding, protein binding; bridging, structural molecule activity
209356_x_at	0.5664	0.0027	0.4818	0.0008	EFEMP2	EGF-containing fibulin-like extracellular matrix protein 2	Calcium ion binding, extracellular matrix structural constituent, protein binding, transmembrane receptor activity
209758_s_at	1.4195	0.0001	0.5778	0.0087	MFAP5	Microfibrillar associated protein 5	Extracellular matrix structural constituent
213290_at	0.832	0.0002	0.5142	0.004	COL6A2	Collagen; type VI; alpha 2	Extracellular matrix structural constituent, protein binding, protein binding; bridging, structural molecule activity
213764_s_at	1.8425	0.0001	0.8102	0.0034	MFAP5	Microfibrillar-associated protein 5	Extracellular matrix structural constituent
214702_at	0.8698	0.0001	0.3948	0.01	FN1	Fibronectin 1	Collagen binding, extracellular matrix structural constituent, heparin binding, protein binding
215076_s_at	1.4494	0.0001	0.5177	0.0031	COL3A1	Collagen; type III; alpha 1 (Ehlers-Danlos syndrome type IV; autosomal dominant)	Extracellular matrix structural constituent, structural molecule activity
221900_at	0.8558	0.0001	0.3936	0.0014	COL8A2	Collagen; type VIII; alpha 2	Extracellular matrix structural constituent, protein binding, protein binding; bridging, structural molecule activity

Figure 1 A published transcriptome dataset of urothelial carcinoma (GSE31684) from GEO database showed gene expression associated with extracellular matrix structure constituent (GO:0005201). COMP is the most upregulated gene.

Figure 2 The COMP transcript level was significantly higher among tumors with high pT status (pT2–pT4) compared with noninvasive tumors (pTa-T1) in UBUC groups. [asterisk (*): extreme outliers; circle (O), mild outliers].

Table 2 Correlation Between COMP Expression and Other Important Clinicopathological Features in Urothelial Carcinomas

Parameter	Category	Upper Urinary Tract Urothelial Carcinoma				Urinary Bladder Urothelial Carcinoma
		Case No.	COMP Expression		p-value	Case No.	COMP Expression		p-value
			Low	High			Low	High
Gender	Male	158	78	80	0.828	216	103	113	0.223
	Female	182	92	90		79	44	35
Age (years)	<65	138	71	67	0.659	121	56	65	0.309
	≥65	202	99	103		174	91	83
Tumor location	Renal pelvis	141	65	76	0.215	–	–	–	–
	Ureter	150	83	67		–	–	–	–
	Renal pelvis and ureter	49	22	27		–	–	–	–
Multifocality	Single	278	142	136	0.399	–	–	–	–
	Multifocal	62	28	34		–	–	–	–
Primary tumor (T)	Ta	89	65	24	<0.001*	84	62	22	<0.001*
	T1	92	59	33		88	52	36
	T2–T4	159	46	113		123	33	90
Nodal metastasis	Negative (N0)	312	164	148	0.002*	266	142	124	<0.001*
	Positive (N1–N2)	28	6	22		29	5	24
Histological grade	Low grade	56	42	14	<0.001*	56	37	19	0.007*
	High grade	284	128	156		239	110	129
Vascular invasion	Absent	234	149	85	<0.001*	246	141	105	<0.001*
	Present	106	21	85		49	6	43
Perineural invasion	Absent	321	167	154	0.002*	275	143	131	0.006*
	Present	19	3	16		20	4	16
Mitotic rate (per 10 high-power fields)	<10	173	99	74	0.007*	139	81	58	0.006*
	≥10	167	71	96		156	66	90

Note: *Statistically significant.

Figure 3 Increased COMP in muscle invasive (B) compared to non-muscle invasive (A) urothelial carcinoma (immunohistochemical staining). (Inset: tumor adjacent non-tumor urothelium) (original magnification: 400×).

Table 3 Univariate Log Rank and Multivariate Analyses for Disease-Specific and Metastasis-Free Survival in Upper Urinary Tract Urothelial Carcinoma

Parameter	Category	Case No.	Disease-Specific Survival					Metastasis-Free Survival
			Univariate Analysis		Multivariate Analysis			Univariate Analysis		Multivariate Analysis
			No. of Events	P-value	RR	95% CI	p-value	No. of Events	p-value	RR	95% CI	P-value
Gender	Male	158	28	0.8286	–	–	–	32	0.7904	–	–	–
	Female	182	33		–	–	–	38		–	–	–
Age (years)	<65	138	26	0.9943	–	–	–	30	0.8470	–	–	–
	≥65	202	35		–	–	–	40		–	–	–
Tumor side	Right	177	34	0.7366	–	–	–	38	0.3074	–	–	–
	Left	154	26		–	–	–	32		–	–	–
	Bilateral	9	1		–	–	–	0		–	–	–
Tumor location	Renal pelvis	141	24	0.0079*	1	–	0.613	31	0.0659	–	–	–
	Ureter	150	22		0.638	0.175–2.327		25		–	–	–
	Renal pelvis and ureter	49	15		0.519	0.130–2.066		14		–	–	–
Multifocality	Single	273	48	0.0026*	1	–	0.405	52	0.0127*	1	–	0.111
	Multifocal	62	18		2.152	0.486–5.965		18		2.384	1.400–3.257
Primary tumor (T)	Ta	89	2	<0.0001*	1	–	0.078	4	<0.0001*	1	–	0.265
	T1	92	9		3.194	0.670–15.225		15		2.577	0.826–8.040
	T2–T4	159	50		5.297	1.156–24.275		51		2.193	0.689–6.979
Nodal metastasis	Negative (N0)	312	42	<0.0001*	1	–	<0.001*	55	<0.0001*	1	–	0.001*
	Positive (N1–N2)	28	19		5.148	2.782–9.526		15		2.940	1.566–5.518
Histological grade	Low grade	56	4	0.0215*	1	–	0.077*	3	0.0027*	1	–	0.066
	High grade	284	57		2.769	0.896–8.554		67		3.219	0.925–11.207
Vascular invasion	Absent	234	24	<0.0001*	1	–	0.304	26	<0.0001*	1	–	0.030*
	Present	106	37		1.387	0.743–2.590		44		1.994	1.070–3.716
Perineural invasion	Absent	321	50	<0.0001*	1	–	<0.001*	61	<0.0001*	1	–	0.015*
	Present	19	11		3.774	1.767–8.062		9		2.640	1.945–8.516
Mitotic rate (per 10 high-power fields)	< 10	173	27	0.167	–	–		30	0.0823	–	–
	≥ 10	167	34		–	–		40		–	–
COMP expression	Low	170	11	<0.0001*	1	–	0.027*	10	<0.0001*	1	–	<0.001*
	High	170	50		2.283	1.100–4.735		60		4.070	1.945–8.516

Note: *Statistically significant.

Table 4 Univariate Log Rank and Multivariate Analyses for Disease-Specific and Metastasis-Free Survival in Urinary Bladder Urothelial Carcinoma

Parameter	Category	Case No.	Disease-Specific Survival					Metastasis-Free Survival
			Univariate analysis		Multivariate Analysis			Univariate Analysis		Multivariate Analysis
			No. of Events	P-value	RR	95% CI	P-value	No. of Events	P-value	RR	95% CI	P-value
Gender	Male	216	41	0.4446	–	–	–	60	0.2720	–	–	–
	Female	79	11		–	–	–	16		–	–	–
Age (years)	<65	121	17	0.1136	–	–	–	31	0.6875	–	–	–
	≥65	174	35		–	–	–	45		–	–	–
Primary tumor (T)	Ta	84	1	<0.0001*	1	–	0.033*	4	<0.0001*	1	–	0.033*
	T1	88	9		4.595	0.530–39.847		23		3.326	1.062–10.413
	T2–T4	123	42		19.886	2.363–167.335		49		4.688	1.456–15.100
Nodal metastasis	Negative (N0)	266	41	0.0002*	1	–	0.585	61	<0.0001*	1	–	0.023*
	Positive (N1–N2)	29	11		1.218	0.600–2.470		15		2.038	1.103–3.765
Histological grade	Low grade	56	2	0.0013*	1	–	0.797	5	0.0007*	1	–	0.621
	High grade	239	50		1.225	0.261–5.742		71		1.291	0.468–3.562
Vascular invasion	Absent	246	37	0.0024*	1	–	0.034*	54	0.0001*	1	–	0.490
	Present	49	15		0.480	0.244–0.947		22		0.813	0.453–1.462
Perineural invasion	Absent	275	44	0.0001*	1	–	0.029*	66	0.0007*	1	–	0.217
	Present	20	8		2.474	1.098–5.579		10		1.562	0.770–3.171
Mitotic rate (per 10 high-power fields)	<10	139	12	<0.0001*	1	–	0.063	23	<0.0001*	1	–	0.123
	≥10	156	40		1.899	0.967–3.731		53		1.499	0.896–2.508
COMP expression	Low	147	8	<0.0001*	1	–	<0.001*	10	<0.0001*	1	–	<0.001*
	High	148	44		3.986	1.815–8.754		66		6.813	3.406–13.625

Note: *Statistically significant.

Figure 4 Kaplan–Meier analysis showed COMP overexpression associated with worse disease-specific survival and metastases-free survival in patients with upper tract urothelial carcinoma (A and B, respectively) and urinary bladder urothelial carcinoma (C and D, respectively).