Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors

Farnedi, Anna; Rossi, Silvia; Bertani, Nicoletta; Gulli, Mariolina; Silini, Enrico Maria; Mucignat, Maria Teresa; Poli, Tito; Sesenna, Enrico; Lanfranco, Davide; Montebugnoli, Lucio; Leonardi, Elisa; Marchetti, Claudio; Cocchi, Renato; Ambrosini-Spaltro, Andrea; Foschini, Maria Pia; Perris, Roberto

doi:10.1186/s12885-015-1336-4

Table 3 Univariate analysis of PG expression in relation to known prognostic indicators

From: Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors

Prognostic indicator/PG			N_.of cases	Clinical outcomes
				Loco-regional recurrence		Lymphnodal metastasis		Distant metastasis		Disease-related death		Any of the clinical outcomes¹
				% cases	p value	% cases	p value	% cases	p value	% cases	p value	% cases	p value
Prognostic indicator
Sex		Male	99	14.1	0.342	15.2	0.043	10.1	0.847	22.2	0.155	36.4	0.094
Sex		Female	74	7.0	0.342	5.4	0.043	9.5	0.847	13.5	0.155	24.3	0.094
Age		≤45 yrs	17	11.8	0.689	11.8	0.964	0.0	-	5.9	0.146	17.6	0.184
Age		>45 yrs	156	12.2	0.689	10.9	0.964	10.9	-	19.9	0.146	32.7	0.184
Smoking		No	66	13.6	0.689	9.1	0.466	9.1	0.718	12.1	0.109	25.8	0.253
Smoking		Yes	105	11.4	0.689	12.4	0.466	10.5	0.718	21.9	0.109	34.3	0.253
Alcohol²		No	83	10.8	0.521	8.4	0.231	4.8	0.026	6.0	<0.001	21.7	0.012
Alcohol²		Yes	88	13.6	0.521	13.6	0.231	14.8	0.026	29.5	<0.001	39.8	0.012
Familial cancer history		No	144	12.5	0.732	10.4	0.615	9.7	0.880	18.8	0.876	31.3	0.994
Familial cancer history		Yes	27	11.1	0.732	14.8	0.615	11.1	0.880	18.5	0.876	33.3	0.994
Precancerous lesions		No	121	12.4	0.869	5.8	0.003	9.9	0.970	18.2	0.869	28.1	0.305
Precancerous lesions		Yes	51	11.8	0.869	21.6	0.003	9.8	0.970	19.6	0.869	37.3	0.305
Tumor site		OC	156	12.2	0.530	11.5	0.204	10.3	0.776	17.9	0.858	31.4	0.399
		OP	14	7.1		0.0		7.1		21.4		21.4
		OC+OP	3	33.3		33.3		0.0		33.3		66.7
T classification		T1	51	3.9	0.007	7.8	0.326	2.0	0.073	5.9	0.038	17.6	0.018
		T2	60	8.3		8.3		16.7		21.7		30.0
		T3	17	23.5		17.6		5.9		23.5		47.1
		T4	45	22.2		15.6		11.1		26.7		42.2
		T1-T2	111	6.3	0.001	8.1	0.065	9.9	0.957	14.4	0.043	24.3	0.005
		T3-T4	62	22.6	0.001	16.1	0.065	9.7	0.957	25.8	0.043	43.5	0.005
N classification		Negative	97	9.3	0.079	5.2	0.001	5.2	0.016	9.3	<0.001	19.6	<0.001
N classification		Positive	76	15.8	0.079	18.4	0.001	15.8	0.016	30.3	<0.001	46.1	<0.001
Differentiation Degree		Well	20	15.0	0.441	0.0	0.223	5.0	0.392	15.0	0.952	20.0	0.44
		Moderate	50	16.0		12.0		14.0		18.0		36.0
		Poor	78	7.7		12.8		7.7		16.7		30.8
Radiotherapy		No	83	8.4	0.082	4.8	0.005	3.6	0.007	8.4	<0.001	20.5	0.002
		Yes	90	15.6		16.7		15.6		27.8		41.1
PG (mRNA) ³
SDC1		↓ / =	61	11.5	0.553	6.6	0.396	4.9	0.016	11.5	0.036	21.3	0.013
SDC1		↑	58	13.8		10.3		19.0		25.9		41.4
SDC2		↓ / =	19	5.3	0.253	5.3	0.519	5.3	0.329	10.5	0.314	15.8	0.104
SDC2		↑	100	14.0		9.0		13.0		20.0		34.0
SDC3		↓ / =	24	8.3	0.405	8.3	0.896	4.2	0.193	20.8	0.855	25.0	0.352
SDC3		↑	95	13.7		8.4		13.7		17.9		32.6
SDC4		↓ / =	19	5.3	0.253	5.3	0.519	5.3	0.329	15.8	0.780	26.3	0.601
SDC4		↑	100	14.0		9.0		13.0		19.0		32.0
GPC1		=	62	12.9	0.803	6.5	0.502	12.9	0.668	17.7	0.940	32.3	0.625
GPC1		↓ / ↑	57	12.3	0.803	10.5	0.502	10.5	0.668	19.3	0.940	29.8	0.625
GPC2		=	76	10.5	0.393	6.6	0.363	10.5	0.596	21.1	0.335	27.6	0.307
GPC2		De novo	43	16.3	0.393	11.6	0.363	14.0	0.596	14.0	0.335	37.2	0.307
GPC3		↓	26	7.7	0.437	0.0	0.219	11.5	0.378	11.5	0.303	23.1	0.624
		=	25	20.0		12.0		4.0		12.0		32.0
		↑	68	11.8		10.3		14.7		23.5		33.8
GPC4		=	81	11.1	0.598	7.4	0.647	13.6	0.365	21.0	0.308	33.3	0.348
GPC4		↓ / ↑	38	15.8	0.598	10.5	0.647	7.9	0.365	13.2	0.308	26.3	0.348
GPC5		=	33	12.1	0.995	9.1	0.851	6.1	0.241	15.2	0.609	30.3	0.986
GPC5		De novo	86	12.8	0.995	8.1	0.851	14.0	0.241	19.8	0.609	31.4	0.986
GPC6		↓	36	19.4	0.351	8.3	0.994	8.3	0.495	16.7	0.838	36.1	0.824
		=	24	8.3		8.3		8.3		16.7		29.2
		↑	59	10.2		8.5		15.3		20.3		28.8
NG2/CSPG4		=	34	2.9	0.029	8.8	0.914	8.8	0.487	14.7	0.401	20.6	0.077
NG2/CSPG4		De novo	85	16.5	0.029	8.2	0.914	12.9	0.487	20.0	0.401	35.3	0.077
PG (Protein) ⁴
SDC1 Tumor cells		Negative	14	7.1	0.447	21.4	0.312	7.1	0.769	7.1	0.269	35.7	0.947
SDC1 Tumor cells		Positive	149	13.4	0.447	10.7	0.312	9.4	0.769	19.5	0.269	31.5	0.947
Stroma		Negative	129	13.2	0.962	11.6	0.812	9.3	0.998	17.1	0.294	31.0	0.429
Stroma		Positive	34	11.8	0.962	11.8	0.812	8.8	0.998	23.5	0.294	35.3	0.429
SDC2 Tumor cells		Negative	143	13.3	0.783	11.9	0.875	8.4	0.303	18.9	0.792	30.8	0.385
SDC2 Tumor cells		Positive	19	10.5	0.783	10.5	0.875	15.8	0.303	15.8	0.792	42.1	0.385
Stroma		Negative	43	9.3	0.277	2.3	0.015	2.3	0.062	2.3	0.001	14.0	0.002
Stroma		Positive	120	14.2	0.277	15.0	0.015	11.7	0.062	24.2	0.001	38.3	0.002
SDC3 Tumor cells		Negative	106	13.2	0.923	12.3	0.793	8.5	0.655	17.9	0.758	30.2	0.575
SDC3 Tumor cells		Positive	56	12.5	0.923	10.7	0.793	10.7	0.655	19.6	0.758	35.7	0.575
SDC4 Tumor cells		Negative	131	15.3	0.071	13.0	0.329	9.2	0.957	17.6	0.588	32.8	0.649
SDC4 Tumor cells		Positive	32	3.1	0.071	6.3	0.329	9.4	0.957	21.9	0.588	28.1	0.649
GPC1 Tumor cells		Negative	44	11.4	0.653	15.9	0.340	4.4	0.214	15.6	0.602	31.8	0.825
GPC1 Tumor cells		Positive	108	13.6	0.653	10.2	0.340	10.7	0.214	18.9	0.602	32.2	0.825
Stroma		Negative	149	11.4	0.007	12.1	0.884	8.4	0.319	16.8	0.012	30.9	0.104
Stroma		Positive	13	30.8	0.007	7.7	0.884	15.4	0.319	38.5	0.012	46.2	0.104
GPC3 Tumor cells		Negative	133	12.8	0.805	12.0	0.841	9.6	0.584	18.4	0.834	33.1	0.605
GPC3 Tumor cells		Positive	30	13.3	0.805	10.0	0.841	6.3	0.584	15.6	0.834	26.7	0.605
GPC4 Tumor cells		Negative	96	13.5	0.969	10.2	0.493	9.2	0.928	17.3	0.716	33.3	0.794
GPC4 Tumor cells		Positive	66	12.1	0.969	13.0	0.493	8.7	0.928	18.8	0.716	30.3	0.794
Stroma		Negative	131	13.0	0.860	11.5	0.692	9.2	0.900	18.3	0.771	32.8	0.810
Stroma		Positive	31	12.9	0.860	12.9	0.692	9.7	0.900	19.4	0.771	29.0	0.810
GPC6 Tumor cells		Negative	101	12.9	0.860	6.9	0.010	5.9	0.052	15.8	0.222	27.7	0.102
GPC6 Tumor cells		Positive	61	13.1	0.860	19.7	0.010	14.8	0.052	23.0	0.222	39.3	0.102
Stroma		Negative	146	11.6	0.058	12.3	0.599	10.3	-	18.5	0.844	32.2	0.828
Stroma		Positive	16	25.0	0.058	6.3	0.599	0.0	-	18.8	0.844	31.3	0.828
NG2/CSPG4 Tumor cells		Negative	52	15.4	0.665	9.6	0.406	9.6	0.923	17.3	0.563	34.6	0.967
NG2/CSPG4 Tumor cells		Positive	100	12.0	0.665	14.0	0.406	10.0	0.923	21.0	0.563	33.0	0.967
T group/NG2/CSPG4 mRNA⁵	T1-T2/=		21	0	<0.001
	T1-T2 / De novo		49	6.1
	T3-T4/=		13	7.7
	T3-T4/De novo		36	30.6
Precancerous lesions/SDC2 stroma	-/-		29			0	0.001
	-/+		84			8.3
	+/-		14			7.1
	+/+		35			28.6
N status⁶/SDC1 mRNA	Negative/↓/=		31					0	0.004
	Negative/↑		30					10.0
	Positive/↓/=		30					10.0
	Positive/↑		28					28.6
N status/SDC2 stroma	-/-		33							0	<0.001
	-/+		57							14.0
	+/-		10							10.0
	+/+		63							33.3
N status/SDC1 mRNA	Negative/↓/=		31									3.2	<0.001
	Negative/↑		57									33.3
	Positive/↓/=		10									40.0
	Positive/↑		63									50.0
PGs pattern
SDC1 mRNA ↑ NG2/CSPG4 mRNA de novo + SDC2 stroma	Yes		36	16.7	0.271	11.1	0.405	25	<0.001	33.3	0.002	50	<0.001
SDC1 mRNA ↑ NG2/CSPG4 mRNA de novo + SDC2 stroma	No		73	12.3	0.271	8.2	0.405	4.1	<0.001	11	0.002	23.3	<0.001

¹This refers to the situation in which patients manifested at least one of the four adopted clinical outcomes within the follow-up period;
²Excessive alcohol consumption was based upon self-provided information;
³PG transcript expression was defined as “↓”, down-regulated; “↑”, up-regulated; “=”, not changed; and “De novo”, de novo expressed, when compared to a healthy mucosal tissues pool that was used as sample calibrator;
⁴Protein expression data are reported as detectable or non-detectable by indirect immunohistochemistry;
⁵Univariate analyses combining the prognostic indicators that were deemed to be independent poor predictors of each of the five clinical outcomes as accomplished through the Cox proportional hazard model;
⁶ N status positive or negative is according to N classification AJCC staging system;
p values <0,05 were considered to be significant (in bold); p values within ≥ 0,05 and <0,06 were considered borderline and were included in the following multivariate regression model; p value was not calculated where a monotone likelihood was established.
Abbreviations: OC, oral cavity; OP, oropharynx.

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