Talc Use, Variants of the GSTM1, GSTT1, and NAT2 Genes, and Risk of Epithelial Ovarian Cancer

Margaret A. Gates; Shelley S. Tworoger; Kathryn L. Terry; Linda Titus-Ernstoff; Bernard Rosner; Immaculata De Vivo; Daniel W. Cramer; Susan E. Hankinson

doi:10.1158/1055-9965.EPI-08-0399

DOI: 10.1158/1055-9965.EPI-08-0399 Published September 2008

Article Figures & Data

Tables

Additional Files

Table 1.

Characteristics of ovarian cancer cases and controls in the NECC and the NHS

Characteristic	NECC					NHS*
Characteristic		Cases	Controls	P^†	Cases	Controls	P^†
N	1,175	1,202		210	600
Mean (SD)
Age (y)^‡	51 (13)	51 (13)	0.37	62 (8)	62 (8)	0.93
Parity among parous women	2.5 (1.3)	2.8 (1.5)	<0.001	3.0 (1.3)	3.4 (1.5)	0.004
Duration oral contraceptive use (mo)^§	52 (54)	61 (55)	0.006	46 (42)	53 (49)	0.22
BMI (kg/m²)	26.3 (6.3)	25.7 (5.5)	0.02	25.7 (5.0)	25.7 (4.5)	0.94
Duration PMH use (mo)^§	78 (86)	74 (71)	0.64	96 (84)	85 (68)	0.18
Duration of lactation (mo)^∥	5.0 (10.0)	7.3 (13.2)	<0.001	6.0 (10.3)	7.2 (9.7)	0.17
Percent of study population
Parous	68	81	<0.001	89	93	0.05
Ever user of oral contraceptives	48	60	<0.001	42	45	0.57
History of tubal ligation	14	18	0.007	14	21	0.02
Ever user of PMH	17	20	0.14	71	63	0.02
Family history of ovarian cancer	5.1	2.8	0.004	9.1	3.7	0.002
Any history of genital talc use	29	24	0.003	40	39	0.79
Regular genital talc use (once a week or more)	27	20	<0.001	29	24	0.15
Daily genital talc use	16	12	0.006	18	13	0.08
Genotype frequencies, %
GSTM1 null	51	53	0.42	48	52	0.36
GSTT1 null	21	22	0.85	19	21	0.45
NAT2 slow acetylator^¶	63	64	0.74	59	67	0.05

↵* In the NHS, duration of lactation was collected in 1986, family history of ovarian cancer was first collected in 1992, and history of genital talc use was collected in 1982; for variables collected on multiple questionnaires, the value from two cycles (2-4 y) before the date of diagnosis for each case was used for the case and their matched controls.
↵† P values calculated using proc t test (continuous variables) or a χ² test (binary variables).
↵‡ Cases and controls in each study population were matched (NHS) or frequency-matched (NECC) on age.
↵§ Duration of oral contraceptive use and PMH use among ever users.
↵∥ Total duration among parous women.
↵¶ NAT2 acetylation genotype based on analysis of three single nucleotide polymorphisms, I114T, R197Q, and G286E.

Table 2.

Characteristics of participants in the NECC and the NHS by history of regular genital talc use (at least once a week)

Characteristic	NECC					NHS*
Characteristic		No regular talc use	Regular talc use	P^†	No regular talc use	Regular talc use	P^†
Mean (SD)
Age (y)	50 (13)	53 (12)	<0.001	61 (8)	62 (8)	0.64
Parity among parous women	2.7 (1.4)	2.7 (1.4)	0.64	3.2 (1.4)	3.3 (1.5)	0.42
Age at first birth among parous women	25.0 (5.1)	24.6 (4.9)	0.22	25.0 (3.5)	24.4 (3.0)	0.03
Duration oral contraceptive use (mo)^‡	58 (55)	54 (54)	0.24	53 (49)	43 (42)	0.08
BMI (kg/m²)	25.7 (5.7)	27.0 (6.4)	<0.001	25.6 (4.6)	26.2 (4.8)	0.13
Duration PMH use (mo)^‡	75 (74)	78 (86)	0.68	90 (74)	83 (70)	0.38
Duration of lactation (mo)^§	6.4 (12.1)	5.8 (11.5)	0.32	7.2 (10.2)	6.3 (9.6)	0.34
Physical activity (h/wk)	2.8 (5.0)	2.4 (3.8)	0.06	3.0 (2.3)	3.1 (2.4)	0.61
Percent of study population
Parous	74	75	0.75	93	92	0.81
Ever user of oral contraceptives	55	50	0.03	44	44	0.96
History of tubal ligation	16	16	0.97	22	13	0.008
Postmenopause	45	54	<0.001	81	81	0.86
Ever user of PMH	17	26	<0.001	66	64	0.73
Ever smoker	53	55	0.35	57	47	0.02
Family history of ovarian cancer	3.9	4.1	0.82	4.5	6.4	0.31
Genotype frequencies, %
GSTM1 null	52	52	0.72	51	49	0.66
GSTT1 null	21	22	0.59	22	17	0.15
NAT2 slow acetylator^∥	63	66	0.23	65	63	0.58

↵* In the NHS, duration of lactation was collected in 1986, family history of ovarian cancer was first collected in 1992, and history of genital talc use was collected in 1982; for variables collected on multiple questionnaires, the value from two cycles (2-4 y) before the date of diagnosis for each case was used for the case and their matched controls.
↵† P values calculated using proc ttest (continuous variables) or a χ² test (binary variables).
↵‡ Duration of oral contraceptive use and PMH use among ever users.
↵§ Total duration among parous women.
↵∥ NAT2 acetylation genotype based on analysis of three single nucleotide polymorphisms, I114T, R197Q, and G286E.

Table 3.

RR (95% CI) for the association between genital talc use and ovarian cancer risk in the NECC and the NHS

	NECC*					NHS*
		Cases (%)	Controls (%)	RR (95% CI)	Cases (%)	Controls (%)	RR (95% CI)	RR (95% CI)
Total epithelial ovarian cancer:
N^‡	1,175	1,202		210	600
Regular genital talc use (once a week or more)
No	859 (73.2)	957 (79.7)	1.00 (reference)	138 (70.8)	414 (76.0)	1.00 (reference)	1.00 (reference)
Yes	314 (26.8)	244 (20.3)	1.40 (1.15-1.70)	57 (29.2)	131 (24.0)	1.24 (0.83-1.83)	1.36 (1.14-1.63)
Frequency of genital talc use
Never	832 (70.9)	916 (76.3)	1.00 (reference)	120 (61.5)	352 (64.6)	1.00 (reference)	1.00 (reference)
Less than once a week	27 (2.3)	41 (3.4)	0.72 (0.43-1.19)	18 (9.2)	62 (11.4)	0.98 (0.54-1.79)	0.82 (0.55-1.20)
1-6 times a week	123 (10.5)	96 (8.0)	1.33 (1.00-1.79)	22 (11.3)	61 (11.2)	1.01 (0.57-1.79)	1.26 (0.97-1.63)
Daily	191 (16.3)	148 (12.3)	1.41 (1.10-1.79)	35 (18.0)	70 (12.8)	1.44 (0.88-2.37)	1.41 (1.14-1.76)
P_trend^§			0.002			0.18	<0.001
Serous invasive ovarian cancer:
N^‡	450	1,202		93	263
Regular genital talc use (once a week or more)
No	310 (69.0)	957 (79.7)	1.00 (reference)	60 (68.2)	177 (73.8)	1.00 (reference)	1.00 (reference)
Yes	139 (31.0)	244 (20.3)	1.62 (1.26-2.09)	28 (31.8)	63 (26.3)	1.48 (0.82-2.68)	1.60 (1.26-2.02)
Frequency of genital talc use
Never	299 (66.6)	916 (76.3)	1.00 (reference)	54 (61.4)	151 (62.9)	1.00 (reference)	1.00 (reference)
Less than once a week	11 (2.4)	41 (3.4)	0.65 (0.32-1.33)	6 (6.8)	26 (10.8)	0.79 (0.29-2.11)	0.70 (0.39-1.24)
1-6 times a week	56 (12.5)	96 (8.0)	1.56 (1.08-2.26)	12 (13.6)	25 (10.4)	1.64 (0.71-3.79)	1.58 (1.12-2.21)
Daily	83 (18.5)	148 (12.3)	1.61 (1.18-2.20)	16 (18.2)	38 (15.8)	1.34 (0.65-2.76)	1.56 (1.17-2.08)
P_trend^§			<0.001			0.29	<0.001

↵* Unconditional (NECC) and conditional (NHS) logistic regression adjusted for age, study center (NECC only), duration of oral contraceptive use (months), parity (continuous), tubal ligation, BMI (kg/m², continuous), and duration of PMH use (months).
↵† P values for tests for heterogeneity comparing the NECC and NHS results were all >0.38.
↵‡ Frequencies do not add up to total N due to missing data on talc use.
↵§ Weighted by the midpoint of each category of genital talc use frequency and calculated using the Wald test.

Table 4.

RR (95% CI) for the association between GSTM1, GSTT1, and NAT2 genotype and epithelial ovarian cancer risk in the NECC and the NHS

	NECC*					NHS*
		Cases (%)	Controls (%)	RR (95% CI)	Cases (%)	Controls (%)	RR (95% CI)	RR (95% CI)
N^‡	1,175	1,202		210	600
GSTM1 genotype
Present	573 (49.1)	567 (47.4)	1.00 (reference)	102 (52.3)	268 (48.5)	1.00 (reference)	1.00 (reference)
Null	594 (50.9)	628 (52.6)	0.93 (0.79-1.10)	93 (47.7)	285 (51.5)	0.83 (0.58-1.17)	0.91 (0.78-1.06)
GSTT1 genotype
Present	919 (78.8)	938 (78.5)	1.00 (reference)	157 (81.3)	439 (78.8)	1.00 (reference)	1.00 (reference)
Null	247 (21.2)	257 (21.5)	0.98 (0.80-1.21)	36 (18.7)	118 (21.2)	0.87 (0.57-1.33)	0.96 (0.80-1.16)
NAT2 genotype
Rapid/intermediate acetylator	387 (36.8)	405 (36.1)	1.00 (reference)	77 (41.0)	182 (33.0)	1.00 (reference)	1.00 (reference)
Slow acetylator	665 (63.2)	717 (63.9)	0.97 (0.81-1.15)	111 (59.0)	369 (67.0)	0.65 (0.45-0.95)	0.82 (0.57-1.20)
Combined GSTM1/GSTT1 genotype
Both present	445 (38.2)	430 (36.0)	1.00 (reference)	81 (44.3)	206 (39.2)	1.00 (reference)	1.00 (reference)
M1 null, T1 present	474 (40.7)	508 (42.5)	0.91 (0.76-1.10)	68 (37.2)	208 (39.5)	0.82 (0.54-1.22)	0.89 (0.75-1.06)
M1 present, T1 null	128 (11.0)	137 (11.5)	0.94 (0.71-1.24)	17 (9.3)	49 (9.3)	0.98 (0.52-1.84)	0.94 (0.73-1.22)
Both null	119 (10.2)	120 (10.0)	0.94 (0.70-1.26)	17 (9.3)	63 (12.0)	0.65 (0.34-1.24)	0.88 (0.67-1.15)
Combined GSTM1/NAT2 genotype
GSTM1 present, NAT2 rapid	195 (18.6)	188 (16.9)	1.00 (reference)	37 (21.0)	85 (16.4)	1.00 (reference)	1.00 (reference)
GSTM1 null, NAT2 rapid	189 (18.1)	214 (19.2)	0.82 (0.61-1.09)	35 (19.9)	91 (17.5)	0.96 (0.53-1.74)	0.84 (0.65-1.09)
GSTM1 present, NAT2 slow	315 (30.1)	343 (30.7)	0.86 (0.66-1.11)	56 (31.8)	161 (31.0)	0.87 (0.51-1.50)	0.86 (0.68-1.09)
GSTM1 null, NAT2 slow	347 (33.2)	371 (33.2)	0.88 (0.68-1.14)	48 (27.3)	183 (35.2)	0.57 (0.33-0.98)	0.76 (0.50-1.14)
Combined GSTT1/NAT2 genotype
GSTT1 present, NAT2 rapid	296 (28.3)	312 (28.0)	1.00 (reference)	52 (29.7)	144 (27.5)	1.00 (reference)	1.00 (reference)
GSTT1 null, NAT2 rapid	88 (8.4)	90 (8.1)	1.03 (0.73-1.45)	17 (9.7)	30 (5.7)	1.55 (0.76-3.16)	1.11 (0.81-1.52)
GSTT1 present, NAT2 slow	519 (49.7)	562 (50.4)	0.97 (0.79-1.19)	90 (51.4)	270 (51.6)	0.87 (0.57-1.33)	0.95 (0.79-1.14)
GSTT1 null, NAT2 slow	142 (13.6)	152 (13.6)	0.98 (0.74-1.31)	16 (9.1)	79 (15.1)	0.51 (0.26-0.99)	0.76 (0.40-1.43)

↵* Unconditional (NECC) and conditional (NHS) logistic regression adjusted for age, study center (NECC only), duration of oral contraceptive use (months), parity (continuous), tubal ligation, BMI (kg/m², continuous), and duration of PMH use (months).
↵† P values for tests for heterogeneity comparing the NECC and NHS results were all >0.06.
↵‡ Frequencies do not add up to total N due to missing genotype data.

Table 5.

Pooled RR (95% CI) for the association between regular talc use and ovarian cancer risk, stratified by genotype, in the NECC and the NHS

	All cancers			Serous invasive cancers			Cases and controls in pooled analysis
	All cancers			Serous invasive cancers						All cases		Serous invasive		Controls
		Regular talc use			Regular talc use			Regular talc			Regular talc		Regular talc
		No	Yes	No	Yes	No	Yes	No	Yes	No	Yes
Gene/stratum
GSTM1 genotype
Present (+)	1.0 (reference)	1.6 (1.2-2.0)	1.0 (reference)	2.0 (1.4-2.8)	480	189	173	90	646	165
Null (-)	1.0 (reference)	1.3 (1.0-1.6)	1.0 (reference)	1.4 (1.0-1.9)	498	179	190	76	690	198
P_interaction*	0.13		0.08
GSTT1 genotype
Present (+)	1.0 (reference)	1.2 (1.0-1.5)	1.0 (reference)	1.5 (1.2-2.0)	785	278	288	129	1,035	301
Null (-)	1.0 (reference)	2.1 (1.4-3.2)	1.0 (reference)	2.4 (1.4-4.0)	194	87	71	38	300	67
P_interaction*	0.03		0.18
NAT2 genotype
Rapid/intermediate acetylator	1.0 (reference)	1.5 (1.1-2.0)	1.0 (reference)	1.9 (1.2-2.8)	330	128	123	57	459	113
Slow acetylator	1.0 (reference)	1.4 (1.1-1.8)	1.0 (reference)	1.6 (1.2-2.1)	552	217	204	96	819	233
P_interaction*	0.60		0.58
GSTM1/GSTT1 genotype^†
GSTM1+, GSTT1+	1.0 (reference)	1.4 (1.0-1.8)	1.0 (reference)	1.7 (1.2-2.5)	378	142	136	68	479	140
GSTM1-, GSTT1+	1.0 (reference)	1.2 (0.9-1.5)	1.0 (reference)	1.4 (0.9-1.9)	400	135	151	60	541	154
GSTM1+, GSTT1-	1.0 (reference)	2.8 (1.6-5.0)	1.0 (reference)	4.8 (2.1-11)	98	47	34	22	158	24
GSTM1-, GSTT1-	1.0 (reference)	1.6 (0.9-2.9)	1.0 (reference)	1.4 (0.6-3.1)	94	40	36	16	138	41
P_interaction*	0.03		0.09

NOTE: NECC: unconditional logistic regression adjusted for age, study center, duration of oral contraceptive use (months), parity (continuous), tubal ligation, BMI (kg/m², continuous), and duration of PMH use (months); NHS: unconditional logistic regression adjusted for age (months), menopausal status at diagnosis (post, pre/dubious), DNA source, duration of oral contraceptive use (months), parity (continuous), tubal ligation, BMI (kg/m², continuous), and duration of PMH use (months). P values for tests for heterogeneity comparing the NECC and NHS results were all >0.36.
↵* P values for interaction based on likelihood ratio test comparing unconditional logistic regression models with and without gene-talc interaction terms.
↵† NHS analysis adjusted for age, menopausal status at diagnosis, and DNA source only to improve stability of estimates.