Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer

Celeste Leigh Pearce; Mary Anne Rossing; Alice W. Lee; Roberta B. Ness; Penelope M. Webb; Georgia Chenevix-Trench; Susan M. Jordan; Douglas A. Stram; Jenny Chang-Claude; Rebecca Hein; Stefan Nickels; Galina Lurie; Pamela J. Thompson; Michael E. Carney; Marc T. Goodman; Kirsten Moysich; Estrid Hogdall; Allan Jensen; Ellen L. Goode; Brooke L. Fridley; Julie M. Cunningham; Robert A. Vierkant; Rachel Palmieri Weber; Argyrios Ziogas; Hoda Anton-Culver; Simon A. Gayther; Aleksandra Gentry-Maharaj; Usha Menon; Susan J. Ramus; Louise Brinton; Nicolas Wentzensen; Jolanta Lissowska; Montserrat Garcia-Closas; Leon F.A.G. Massuger; Lambertus A.L.M. Kiemeney; Anne M. Van Altena; Katja K.H. Aben; Andrew Berchuck; Jennifer A. Doherty; Edwin Iversen; Valerie McGuire; Patricia G. Moorman; Paul Pharoah; Malcolm C. Pike; Harvey Risch; Weiva Sieh; Daniel O. Stram; Kathryn L. Terry; Alice Whittemore; Anna H. Wu; Joellen M. Schildkraut; Susanne K. Kjaer

doi:10.1158/1055-9965.EPI-12-1030-T

DOI: 10.1158/1055-9965.EPI-12-1030-T Published May 2013

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Additional Files

Table 1.

Description of study sites included in the analysis

Study name	Study abbreviation	Country	Study type	Years of collection	Number of controls	Number of cases	Serous^a	Mucinous	Endometrioid	Clear cell	Other^b
Australian Ovarian Cancer Study	AUS	Australia	Population-based	2002–2006	1122	1003	616	39	130	68	150
Diseases of the Ovary and their Evaluation Study	DOV	USA	Population-based	2002–2005	604	530	303	18	84	30	95
German Ovarian Cancer Study	GER	Germany	Population-based	1993–1996	433	203	106	21	22	6	48
Hawaii Ovarian Cancer Study	HAW	USA	Population-based	1993–2008	170	81	43	3	13	6	16
Novel Risk Factors and Potential Early Detection Markers for Ovarian Cancer	HOP	USA	Population-based	2003–2009	388	385	220	19	53	31	62
Malignant Ovarian Cancer Study	MAL	Denmark	Population-based	1994–1999	551	445	274	43	56	33	39
Mayo Clinic Ovarian Cancer Case Control Study^c	MAY	USA	Clinic-based	2000–2007	422	319	205	11	63	22	18
North Carolina Ovarian Cancer Study	NCO	USA	Population-based	1999–2008	655	493	293	20	81	58	41
Nijmegen Ovarian Cancer Study	NTH	Netherlands	Hospital-based	2008	577	243	100	30	60	18	35
Polish Ovarian Cancer Case Control Study^c	POL	Poland	Population-based	2000–2003	228	238	108	23	53	13	41
Family Registry for Ovarian Cancer and Genetic Epidemiology^c	STA	USA	Population-based	1997–2001	413	295	184	18	38	23	32
University of California, Irvine Ovarian Cancer Study^c	UCI	USA	Population-based	1993–2005	494	280	167	17	46	21	29
United Kingdom Ovarian Cancer Population Study^c	UKO	United Kingdom	Hospital-based	2006–2010	852	710	359	71	121	71	88
University of Southern California, Study of Lifestyle and Women's Health	USC	USA	Population-based	1993–2005	465	341	183	26	44	15	73
				Total:	7374	5566	3161	359	864	415	767

↵^a73.4% high-grade, 7.9% low-grade, 18.7% grade unknown.
↵^bIncludes mixed cell, other specified epithelial ovarian cancer, undifferentiated/poorly differentiated epithelial, and unknown but known to be epithelial.
↵^cMissing data for nongenetic variables (MAY missing tubal ligation, UCI missing 30% tubal ligation, POL and STA missing endometriosis, UKO >20% missing oral contraceptive use, endometriosis, tubal ligation, and parity).

Table 2.

Association between each SNP and invasive ovarian cancer among all women and by environmental factors

	rs3814113		rs2072590		rs2665390		rs10088218		rs8170		rs9303542
	OR^a (95% CI)	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b
Main effect: Previously published result (11–13)	0.82 (0.79–0.86)		1.16 (1.12–1.21)		1.19 (1.11–1.27)		0.84 (0.80–0.89)		1.12 (1.07–1.17)		1.11 (1.06–1.16)
Main effect: Current report^c	0.82 (0.77–0.88)		1.13 (1.07–1.19)		1.25 (1.14–1.38)		0.84 (0.78–0.91)		1.07 (1.01–1.14)		1.11 (1.04–1.17)
Endometriosis
Yes	0.84 (0.60–1.16)		1.45 (1.14–1.85)		1.73 (1.10–2.73)		0.78 (0.61–1.01)		1.06 (0.82–1.36)		0.93 (0.71–1.23)
No	0.83 (0.76–0.91)	0.98	1.12 (1.06–1.19)	0.05	1.23 (1.10–1.37)	0.15	0.84 (0.78–0.90)	0.60	1.12 (1.05–1.19)	0.69	1.05 (0.98–1.13)	0.41
First-degree family history
Yes	0.67 (0.46–0.99)		1.01 (0.73–1.38)		0.98 (0.54–1.77)		0.74 (0.47–1.16)		1.07 (1.00–1.15)		1.10 (1.04–1.17)
No	0.83 (0.78–0.88)	0.30	1.13 (1.07–1.19)	0.49	1.25 (1.13–1.37)	0.43	0.84 (0.78–0.92)	0.56	0.92 (0.65–1.32)	0.42	1.08 (0.75–1.57)	0.93
Oral contraceptive use
Never	0.77 (0.70–0.86)		1.06 (0.96–1.16)		1.22 (1.03–1.43)		0.84 (0.73–0.96)		1.10 (0.99–1.23)		1.11 (1.00–1.22)
<1 year	0.82 (0.66–1.02)		1.18 (0.97–1.44)		1.24 (0.88–1.75)		0.79 (0.59–1.04)		0.83 (0.67–1.04)		1.21 (0.99–1.48)
1–1.99 years	1.03 (0.80–1.33)		1.31 (1.03–1.68)		1.68 (1.05–2.67)		0.86 (0.60–1.25)		1.19 (0.89–1.60)		1.27 (0.98–1.65)
2–4.99 years	0.80 (0.67–0.96)		1.15 (0.99–1.34)		1.36 (1.03–1.79)		0.73 (0.58–0.93)		1.00 (0.83–1.20)		1.00 (0.85–1.18)
5–9.99 years	0.87 (0.74–1.03)		1.10 (0.94–1.27)		1.31 (1.01–1.69)		0.80 (0.64–0.99)		1.13 (0.94–1.36)		1.16 (1.00–1.35)
10+ years	0.92 (0.78–1.09)	0.27	1.19 (1.02–1.38)	0.52	1.41 (1.08–1.83)	0.81	0.98 (0.78–1.22)	0.63	1.11 (0.93–1.33)	0.24	1.16 (0.99–1.36)	0.56
Tubal ligation
Yes	0.91 (0.78–1.06)		1.22 (1.06–1.39)		1.23 (0.97–1.54)		0.74 (0.60–0.91)		1.04 (0.97–1.13)		1.13 (1.05–1.20)
No	0.81 (0.76–0.87)	0.21	1.10 (1.03–1.17)	0.21	1.32 (1.18–1.49)	0.55	0.86 (0.78–0.95)	0.19	1.22 (1.04–1.43)	0.09	1.05 (0.92–1.21)	0.42
Parity
No births	0.82 (0.70–0.96)		1.07 (0.93–1.24)		1.20 (0.94–1.53)		0.83 (0.68–1.02)		1.08 (0.91–1.28)		1.08 (0.93–1.26)
1 birth	0.78 (0.66–0.93)		1.15 (0.99–1.33)		1.46 (1.10–1.93)		0.87 (0.69–1.10)		1.05 (0.88–1.26)		1.07 (0.91–1.26)
2–3 births	0.86 (0.79–0.94)		1.12 (1.04–1.21)		1.21 (1.05–1.38)		0.84 (0.75–0.94)		1.11 (1.01–1.22)		1.11 (1.03–1.21)
4–5 births	0.74 (0.61–0.89)		1.25 (1.04–1.49)		1.30 (0.96–1.74)		0.68 (0.52–0.89)		0.96 (0.78–1.17)		1.09 (0.91–1.30)
6+ births	1.23 (0.71–2.14)	0.31	1.28 (0.72–2.27)	0.31	2.26 (0.98–5.19)	0.48	0.80 (0.38–1.69)	0.68	0.74 (0.43–1.30)	0.48	1.09 (0.64–1.87)	0.99
Age
<50 years old	0.83 (0.73–0.94)		1.20 (1.07–1.35)		1.33 (1.08–1.64)		0.82 (0.70–0.97)		0.96 (0.83–1.10)		1.12 (1.00–1.26)
50–54 years old	0.83 (0.71–0.98)		1.12 (0.97–1.30)		1.25 (0.96–1.63)		0.94 (0.75–1.17)		1.07 (0.89–1.28)		1.21 (1.04–1.40)
55–59 years old	0.77 (0.67–0.90)		1.07 (0.94–1.23)		1.17 (0.93–1.47)		0.94 (0.78–1.14)		1.18 (1.01–1.39)		1.03 (0.89–1.18)
60–64 years old	0.80 (0.68–0.93)		1.12 (0.98–1.27)		1.38 (1.10–1.74)		0.84 (0.69–1.02)		1.13 (0.97–1.32)		0.99 (0.86–1.14)
65+ years old	0.87 (0.78–0.98)	0.77	1.11 (1.00–1.23)	0.78	1.25 (1.04–1.50)	0.87	0.78 (0.67–0.91)	0.52	1.09 (0.97–1.22)	0.34	1.17 (1.05–1.30)	0.20

↵^aOR conditioned on race/ethnicity, individual models by site; estimate derived from meta-analysis of individual site models.
↵^bP_het = heterogeneity across strata of environmental factor.
↵^cMain effect of genotype based on a log-additive model.

Table 3.

Association between genetic risk score and ovarian cancer among all women and by environmental factors

	Invasive		Serous		Mucinous		Endometrioid		Clear cell
	OR^a (95% CI)	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b	OR^a 95% CI	P_het^b
All women	2.56 (2.14–3.06)		2.50 (2.13–2.94)		2.61 (1.41–4.81)		3.49 (2.18–5.59)		3.11 (1.31–7.39)
Endometriosis
Yes	4.35 (2.09–9.05)		6.50 (3.10–13.63)		2.88 (0.06–143.62)		6.86 (1.32–35.66)		2.03 (0.13–30.77)
No	2.47 (2.02–3.02)	0.14	2.31 (1.93–2.77)	0.01	2.50 (1.24–5.01)	0.94	3.86 (2.24–6.67)	0.52	3.73 (1.31–10.61)	0.68
First-degree family history
Yes	2.48 (0.87–7.08)		3.02 (1.22–7.44)		0.33 (0.00–61.92)		0.22 (0.01–5.00)		—
No	2.51 (2.09–3.01)	0.98	2.44 (2.06–2.88)	0.65	2.70 (1.44–5.06)	0.43	3.72 (2.29–6.04)	0.08	3.69 (1.53–8.91)
Oral contraceptive use
Never	2.61 (1.92–3.54)		2.76 (2.09–3.63)		1.99 (0.74–5.34)		4.84 (2.24–10.43)		2.02 (0.46–8.91)
<1 year	2.54 (1.36–4.75)		2.35 (1.37–4.03)		4.63 (0.17–123.03)		1.47 (0.19–11.27)		15.18 (0.48–478.27)
1–1.99 years	2.99 (1.40–6.37)		3.03 (1.51–6.06)		15.72 (0.07–3522.25)		0.73 (0.09–6.29)		0.64 (0.01–43.62)
2–4.99 years	2.61 (1.55–4.39)		2.48 (1.55–3.98)		2.67 (0.20–36.47)		1.54 (0.31–7.60)		16.95 (1.17–244.76)
5–9.99 years	2.66 (1.64–4.32)		2.14 (1.37–3.35)		2.93 (0.64–13.43)		5.87 (1.45–23.76)		0.54 (0.03–8.67)
10+ years	2.49 (1.53–4.07)	1.00	1.88 (1.19–2.97)	0.74	0.76 (0.11–5.14)	0.84	6.89 (1.64–28.91)	0.33	0.32 (0.01–11.28)	0.32
Tubal ligation
Yes	2.93 (1.89–4.55)		2.47 (1.69–3.62)		2.18 (0.24–20.32)		5.48 (1.24–24.20)		2.28 (0.13–41.13)
No	2.52 (2.04–3.12)	0.54	2.46 (2.03–2.99)	0.98	2.79 (1.40–5.58)	0.84	4.05 (2.34–7.00)	0.71	5.55 (2.06–14.94)	0.57
Parity
No births	2.15 (1.38–3.36)		2.19 (1.45–3.31)		4.23 (1.07–16.78)		1.40 (0.49–3.97)		2.71 (0.49–14.92)
1 birth	3.07 (1.85–5.10)		2.60 (1.64–4.10)		4.28 (0.79–23.30)		7.07 (1.87–26.69)		3.47 (0.17–69.26)
2–3 births	2.36 (1.84–3.02)		2.29 (1.83–2.87)		2.39 (0.97–5.92)		2.71 (1.32–5.59)		2.30 (0.55–9.72)
4–5 births	4.05 (2.28–7.20)		3.52 (2.14–5.79)		5.39 (0.20–142.90)		9.03 (1.73–47.26)		19.43 (0.31–1206.17)
6+ births	1.91 (0.43–8.59)	0.40	2.04 (0.55–7.56)	0.59	—	0.86	1.58 (0.02–116.21)	0.24	–	0.82
Age
<50 years old	2.64 (1.83–3.80)		2.53 (1.77–3.60)		4.25 (1.39–12.99)		4.64 (1.85–11.61)		4.18 (0.64–27.11)
50–54 years old	2.63 (1.62–4.27)		2.11 (1.36–3.29)		1.30 (0.19–8.79)		3.31 (0.97–11.27)		2.30 (0.18–28.95)
55–59 years old	2.16 (1.41–3.31)		2.16 (1.46–3.18)		3.08 (0.60–15.75)		4.13 (1.32–12.94)		4.86 (0.80–29.46)
60–64 years old	2.61 (1.69–4.04)		2.68 (1.84–3.90)		0.91 (0.15–5.66)		1.85 (0.47–7.34)		4.44 (0.47–42.19)
65+ years old	2.63 (1.88–3.69)	0.96	2.68 (1.99–3.61)	0.84	2.95 (0.88–9.95)	0.63	2.54 (1.01–6.38)	0.80	1.28 (0.15–10.80)	0.89

↵^aOR conditioned on race/ethnicity, individual models by site; estimate derived from meta-analysis of individual site models.
↵^bP_het = heterogeneity across strata of environmental factor.

Table 4.

Association between environmental and genetic factors and ovarian cancer risk in a multiplicative joint effects model

	Invasive		Serous		Mucinous		Endometrioid		Clear cell
	OR^a (95% CI)	P	OR^a 95% CI	P	OR^a 95% CI	P	OR^a 95% CI	P	OR^a 95% CI	P	P_het across histology
Endometriosis
Yes vs. no	1.53 (1.30–1.81)	<0.001	1.17 (0.95–1.44)	0.143	1.54 (0.86–2.74)	0.145	2.40 (1.78–3.23)	<0.001	3.59 (2.50–5.15)	<0.001	<0.001
First-degree family history
Yes vs. no	2.09 (1.70–2.57)	<0.001	2.29 (1.81–2.89)	<0.001	2.40 (1.25–4.61)	0.009	1.96 (1.28–3.00)	0.002	2.15 (0.94–4.92)	0.071	0.929
Oral contraceptive use
1–1.99 years vs. never	0.70 (0.59–0.83)	<0.001	0.80 (0.65–0.98)	0.031	0.75 (0.36–1.57)	0.451	0.64 (0.45–0.92)	0.016	0.76 (0.46–1.24)	0.272	0.798
2–4.99 years vs. never	0.57 (0.50–0.65)	<0.001	0.65 (0.56–0.77)	<0.001	0.56 (0.35–0.90)	0.016	0.45 (0.34–0.60)	<0.001	0.55 (0.37–0.83)	0.004	0.167
5–9.99 years vs. never	0.48 (0.42–0.55)	<0.001	0.53 (0.45–0.62)	<0.001	0.68 (0.46–1.01)	0.054	0.41 (0.31–0.54)	<0.001	0.40 (0.27–0.58)	<0.001	0.097
10+ years vs. never	0.34 (0.30–0.39)	<0.001	0.39 (0.33–0.46)	<0.001	0.48 (0.32–0.72)	<0.001	0.28 (0.21–0.38)	<0.001	0.28 (0.18–0.44)	<0.001	0.083
Tubal ligation
Yes vs. no	0.74 (0.67–0.83)	<0.001	0.84 (0.74–0.95)	0.007	0.65 (0.42–0.99)	0.043	0.57 (0.44–0.73)	<0.001	0.68 (0.47–0.99)	0.046	0.041
Parity
1 birth vs. no births	0.76 (0.66–0.88)	<0.001	0.89 (0.75–1.06)	0.175	0.76 (0.49–1.17)	0.214	0.69 (0.53–0.91)	0.009	0.39 (0.26–0.58)	<0.001	0.002
2 or more births vs. no births	0.58 (0.51–0.65)	<0.001	0.66 (0.58–0.76)	<0.001	0.52 (0.37–0.73)	<0.001	0.42 (0.34–0.53)	<0.001	0.25 (0.18–0.33)	<0.001	<0.001
Risk score quartile
Second vs. first quartile	1.25 (1.12–1.40)	<0.001	1.33 (1.15–1.53)	<0.001	1.72 (1.20–2.48)	0.004	1.25 (0.98–1.59)	0.068	1.19 (0.84–1.69)	0.329	0.463
Third vs. first quartile	1.29 (1.16–1.44)	<0.001	1.36 (1.19–1.56)	<0.001	1.31 (0.91–1.90)	0.151	1.13 (0.89–1.43)	0.321	1.20 (0.86–1.69)	0.289	0.577
Fourth vs. first quartile	1.65 (1.48–1.84)	<0.001	1.85 (1.62–2.11)	<0.001	1.76 (1.24–2.48)	0.001	1.64 (1.31–2.05)	<0.001	1.59 (1.15–2.21)	0.006	0.728

↵^aOR conditioned on age and race/ethnicity, individual models by site; estimate derived from meta-analysis of individual site models.

Additional Files

Tables

Supplementary Data

Files in this Data Supplement:

Supplementary Tables 1 - 6 - PDF file - 97K, Supplementary Table 1. Association between rs3814113 and ovarian cancer among all women and by environmental factors Supplementary Table 2. Association between rs2072590 and ovarian cancer among all women and by environmental factors Supplementary Table 3. Association between rs2665390 and ovarian cancer among all women and by environmental factors Supplementary Table 4. Association between rs10088218 and ovarian cancer among all women and by environmental factors Supplementary Table 5. Association between rs8170 and ovarian cancer among all women and by environmental factors Supplementary Table 6. Association between rs9303542 and ovarian cancer among all women and by environmental factors