Bioinformatic Exploration for Prognostic Significance of Sphingolipid Metabolism-Related Genes in Invasive Ductal Carcinoma Using the Cancer Genome Atlas Cohort

Figures & data

Figure 1 Heat map showing the relative mRNA expression levels of the sphingolipid metabolism-related genes in female IDC tissues and NST obtained from TCGA BRCA cohort. In the data shown in matrix format, each row represents an individual gene and each column represents a single tissue. Each cell in the matrix represents the relative mRNA expression level of a gene feature in an individual tissue. The red and green in the cells reflects relatively high and low expression levels, respectively, as indicated by the scale bar. The samples are sorted into the NST group on the left and the IDC group on the right. Each cells is arranged in descending order of the mean difference between the scaled mRNA expression levels of each gene in the NST and IDC groups.

Abbreviations: TCGA BRCA, The Cancer Genome Atlas breast invasive carcinoma; IDC, invasive ductal carcinoma; NST, normal solid tissues.

Figure 2 (A) Heat map showing significantly altered mRNA expression of the sphingolipid metabolism‑related genes in female IDC tissues compared with female NST obtained from TCGA BRCA cohort. In the data shown in matrix format, each row represents an individual gene and each column represents a single tissue. Each cell in the matrix represents the relative mRNA expression level of a gene feature in an individual tissue. The red and green in the cells represent relatively high and low expression levels, respectively, as indicated by the scale bar. The samples are sorted into the NST group on the left and the IDC group on the right. Each cells is arranged in descending order of the mean difference between the scaled mRNA expression levels of each gene in the NST and IDC groups. *Student’s t-test, P<0.05 (NST versus IDC). (B) Relatively altered mRNA expression levels of various sphingolipid metabolism-related genes in IDC samples obtained from TCGA BRCA. **Student’s t-test, P<0.001, |2FC| ≥ 1.0.

Abbreviations: TCGA BRCA, The Cancer Genome Atlas breast invasive carcinoma; IDC, invasive ductal carcinoma; NST, normal solid tissues.

Figure 3 Survival analysis of the dysregulated sphingolipid metabolism-related genes in IDC samples obtained from TCGA BRCA cohort. Kaplan–Meier estimates of female patients with IDC according to the relative mRNA expression values of GAL3ST1, SMPDL3B, LASS3, LASS2, B4GALT6, HPGD, UGT8, ST8SIA1, S1PR1, LPAR1, B4GALNT1, and LPAR2.

Abbreviations: TCGA BRCA, The Cancer Genome Atlas breast invasive carcinoma; IDC, invasive ductal carcinoma.

Table 1 Upregulated mRNA Expression Levels of Sphingolipid Metabolism-Related Genes in Relation to Clinicopathological Parameters of IDC

	SMPDL3B (Number)			B4GALNT1 (Number)			LPAR2 (Number)			LASS2 (Number)
	Low	High	P	Low	High	P	Low	High	P	Low	High	P
Age			0.002^a			0.120^b			0.931^b			0.003^a
< 50	70	117		93	94		97	90		108	79
≥ 50	224	234		270	208		251	227		214	264
T stage			0.738^a			0.004^a			<0.001^a			0.443^a
T1	86	89		115	60		124	51		88	87
T2	183	208		200	191		182	209		191	200
T3	25	26		27	24		18	33		23	28
T4	9	15		9	15		12	12		8	16
N stage			0.255^a			0.630^a			0.140^a			0.753^a
N0	137	167		172	132		154	150		153	151
N1	107	117		123	101		124	100		102	122
N2	47	37		41	43		48	36		40	44
N3	12	19		16	15		11	20		15	16
M stage			0.105^b			0.582^b			0.781^b			0.580^b
M0	292	335		344	283		329	298		305	322
M1	9	4		6	7		6	7		5	8
ER status			<0.001^a			<0.001^a			<0.001^a			<0.001^a
Negative	47	114		69	92		46	115		134	27
Positive	246	223		280	189		283	186		174	295
PR status			<0.001^a			<0.001^a			<0.001^a			<0.001^a
Negative	81	140		91	130		73	148		152	69
Positive	213	194		257	150		256	151		154	253
HER2			0.054^a			0.028^b			0.155^b			0.446^b
Negative	237	284		281	240		283	238		248	273
Positive	56	44		66	34		46	54		52	48
Subtype according to IHC			<0.001^a			<0.001^a			<0.001^a			<0.001^a
Luminal A	145	148		182	111		195	98		104	189
Luminal B	98	62		80	80		91	69		51	109
HER2-enriched	29	33		41	21		20	42		40	22
TN	27	94		38	83		29	92		108	13

Notes: Luminal A: ER+ or PR+, and HER2-; Luminal B: ER+ or PR+, and HER2+; HER2-enriched: ER-, PR-, and HER2+; TN: ER-, PR-, and HER-^aPearson’s Chi-square Test. ^bFisher’s Exact Test.

Abbreviations: IDC, invasive ductal carcinoma; ER, estrogen receptor; PR, progesterone receptor; HER2, epidermal growth factor receptor type 2; IHC, immunohistochemistry; TN, triple-negative.

Table 2 Downregulated mRNA Expression Levels of Sphingolipid Metabolism-Related Genes in Relation to Clinicopathological Parameters of IDC

	GAL3ST1 (Number)			LASS3 (Number)			B4GALT6 (Number)			HPGD (Number)
	Low	High	p	Low	High	p	Low	High	p	Low	High	p
Age			0.256^b			0.036^b			0.490^b			0.024^b
< 50	116	71		96	91		96	91		87	100
≥ 50	273	205		289	189		260	218		270	208
T stage			0.829^a			0.567^a			0.351^a			0.119^a
T1	108	67		104	71		102	73		81	94
T2	226	165		229	162		200	191		220	171
T3	30	21		25	26		28	23		29	22
T4	15	9		13	11		15	9		15	9
N stage			0.869^a			0.228^a			0.195^a			0.215^a
N0	180	124		181	123		154	150		159	145
N1	132	92		118	106		128	96		122	102
N2	47	37		51	33		44	40		42	42
N3	20	11		21	10		21	10		22	9
M stage			0.779^b			0.573^b			0.400^b			0.780^b
M0	371	256		361	266		336	291		336	291
M1	7	6		9	4		9	4		8	5
ER status			0.003^b			0.356^b			0.006^b			<0.001^a
Negative	77	84		98	63		72	89		14	57
Positive	288	181		265	204		270	199		234	235
PR status			0.011^b			0.312^b			<0.001^a			0.007^b
Negative	113	108		121	100		98	123		135	86
Positive	252	155		240	167		243	164		202	205
HER2			0.149^b			0.740^b			0.003^b			0.155^b
Negative	302	219		300	221		269	252		287	234
Positive	66	34		60	40		68	32		47	53
Subtype according to IHC			<0.001^a			0.041^a			<0.001^a			<0.001^a
Luminal A	190	103		158	135		170	123		136	157
Luminal B	96	64		106	54		82	78		87	73
HER2-enriched	39	23		41	21		47	15		30	32
TN	49	72		68	53		41	80		89	32
	UGT8 (Number)			ST8SIA1 (Number)			S1PR1 (Number)			LPAR1 (Number)
	Low	High	p	Low	High	p	Low	High	p	Low	High	p
Age			0.003^b			0.019^b			0.058^b			0.099^b
< 50	101	86		93	94		89	98		92	95
≥ 50	319	159		287	191		267	211		200	278
T stage			0.127^a			0.008^a			0.089^a			<0.001^a
T1	121	54		98	77		79	96		54	121
T2	239	152		215	176		222	196		188	203
T3	29	22		34	17		30	21		31	20
T4	18	6		21	3		16	8		7	17
N stage			0.029^a			0.809^a			0.287^a			0.724^a
N0	176	128		171	133		170	134		127	177
N1	152	72		128	96		116	108		102	122
N2	61	23		50	34		42	42		40	44
N3	19	12		20	11		21	10		13	18
M stage			1.000^b			0.170^b			0.005^b			0.574^b
M0	397	230		357	270		336	291		272	355
M1	8	5		10	3		12	1		7	6
ER status			<0.001^a			<0.001^a			0.067^b			<0.001^a
Negative	41	120		28	133		95	66		101	60
Positive	358	111		331	138		236	233		175	294
PR status			<0.001^a			<0.001^a			0.211^b			<0.001^a
Negative	84	137		75	146		124	97		131	90
Positive	315	92		284	123		207	200		144	263
HER2			0.003^b			0.187^b			0.744^b			0.443^b
Negative	316	205		290	231		282	239		223	298
Positive	76	24		63	37		56	44		47	53
Subtype according to IHC			<0.001^a			<0.001^a			<0.001^a			<0.001^a
Luminal A	229	64		207	86		121	172		82	211
Luminal B	122	38		121	39		108	52		82	78
HER2-enriched	43	19		33	29		36	26		32	30
TN	9	122		7	114		79	42		84	37

Notes: Luminal A: ER+ or PR+, and HER2-; Luminal B: ER+ or PR+, and HER2+; HER2-enriched: ER-, PR-, and HER2+; TN: ER-, PR-, and HER-^aPearson’s Chi-square Test. ^bFisher’s Exact Test.

Abbreviations: IDC, invasive ductal carcinoma; ER, estrogen receptor; PR, progesterone receptor; HER2, epidermal growth factor receptor type 2; IHC, immunohistochemistry; TN, triple-negative.

Table 3 Spearman Correlation Analysis Between Inter-Individual Components of Sphingolipid Metabolism-Related Genes

Samples	Correlations Between Components	Spearman Correlation Coefficient Value	P-value*
IDC tissues from TCGA BRCA cohort (n = 665)	GAL3ST1 and SMPDL3B	0.108	0.006
	GAL3ST1 and LASS3	0.078	0.046
	GAL3ST1 and LASS2	−0.116	0.003
	GAL3ST1 and HPGD	−0.126	0.001
	GAL3ST1 and ST8SIA1	0.143	<0.001
	GAL3ST1 and S1PR1	−0.083	0.032
	GAL3ST1 and LPAR2	0.109	0.005
	SMPDL3B and LASS2	−0.081	0.036
	SMPDL3B and B4GALT6	−0.099	0.011
	SMPDL3B and HPGD	−0.172	<0.001
	SMPDL3B and UGT8	0.175	<0.001
	SMPDL3B and ST8SIA1	0.145	<0.001
	SMPDL3B and S1PR1	−0.128	0.001
	SMPDL3B and LPAR1	−0.133	0.001
	SMPDL3B and LPAR2	0.324	<0.001
	LASS3 and LASS2	−0.081	0.037
	LASS3 and B4GALT6	0.101	0.009
	LASS3 and UGT8	0.168	<0.001
	LASS3 and S1PR1	0.099	0.010
	LASS3 and LPAR1	−0.092	0.018
	LASS2 and UGT8	−0.359	<0.001
	LASS2 and ST8SIA1	−0.396	<0.001
	LASS2 and B4GALNT1	−0.091	0.019
	LASS2 and LPAR2	−0.127	0.001
	B4GALT6 and UGT8	0.223	<0.001
	B4GALT6 and ST8SIA1	0.086	0.026
	B4GALT6 and S1PR1	−0.083	0.032
	B4GALT6 and B4GALNT1	0.274	<0.001
	B4GALT6 and LPAR2	−0.141	<0.001
	HPGD and UGT8	−0.082	0.034
	HPGD and S1PR1	0.241	<0.001
	HPGD and LPAR1	0.177	<0.001
	HPGD and LPAR2	−0.192	<0.001
	UGT8 and ST8SIA1	0.456	<0.001
	UGT8 and LPAR1	−0.081	0.036
	UGT8 and B4GALNT1	0.178	<0.001
	UGT8 and LPAR2	0.163	<0.001
	ST8SIA1 and B4GALNT1	0.150	<0001
	ST8SIA1 and LPAR2	0.105	0.007
	S1PR1 and LPAR1	0.204	<0.001
	S1PR1 and B4GALNT1	−0.235	<0.001
	S1PR1 and LPAR2	−0.154	<0.001
	LPAR1 and LPAR2	−0.287	<0.001

Note: *Spearman correlation coefficient analysis.