Common Genetic Variation and Susceptibility to Ovarian Cancer: Current Insights and Future Directions

Siddhartha P. Kar; Andrew Berchuck; Simon A. Gayther; Ellen L. Goode; Kirsten B. Moysich; Celeste Leigh Pearce; Susan J. Ramus; Joellen M. Schildkraut; Thomas A. Sellers; Paul D.P. Pharoah

doi:10.1158/1055-9965.EPI-17-0315

DOI: 10.1158/1055-9965.EPI-17-0315 Published April 2018

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Figure 1.
An outline of the most common steps applied in the functional characterization of cancer risk loci. The aim of this pipeline is to identify the genes and associated molecular and cellular pathways through which cancer risk SNPs at each locus are most likely to exert their effects on cancer susceptibility.

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Table 1.

New EOC risk loci identified by the OncoArray meta-analysis at P < 5 × 10⁻⁸ (ref. 23)^a

Locus	Lead SNP	Phenotype	Effect allele	EAF	OR (95% CI)	P
3q22.3	rs112071820	Mucinous	GCCAG	0.28	1.29 (1.20–1.37)	1.5E−13
3q28	rs9870207	S. borderline + LGSOC	A	0.69	1.19 (1.12–1.27)	4.5E−08
4q32.3	rs13113999	S. borderline	T	0.52	1.23 (1.14–1.32)	4.7E−08
5q12.3	rs555025179	Endometrioid	GACAC	0.53	1.18 (1.11–1.26)	4.5E−08
8q21.11	rs150293538	S. borderline + LGSOC	T	0.98	2.19 (1.65–2.90)	2.0E−09
9q31.1	rs320203^b	Mucinous	A	0.85	1.29 (1.18–1.41)	1.7E−08
10q24.33	rs7902587	S. borderline + LGSOC	T	0.10	1.29 (1.18–1.41)	4.0E−08
18q11.2	rs8098244	S. borderline + LGSOC	A	0.28	1.19 (1.12–1.27)	3.9E−08
22q12.1	rs6005807	HGSOC	C	0.90	1.17 (1.10–1.23)	1.2E−08
2q13	rs2165109	HGSOC	C	0.25	1.09 (1.05–1.12)	2.0E−08
8q24.21	rs9886651	HGSOC	G	0.46	1.08 (1.05–1.11)	1.9E−09
12q24.31	rs7953249	HGSOC	G	0.42	1.08 (1.06–1.11)	4.5E−10

Abbreviations: EAF, effect allele frequency; S. borderline, serous borderline.
↵^aIn European ancestry populations.
↵^bAll risk loci listed except rs320203 had BFDP <10%.

Table 2.

Previously published EOC risk loci confirmed by the OncoArray meta-analysis at P < 5 × 10⁻⁸ (ref. 23)^{^a^,^b}

Locus	Lead SNP	Phenotype	Effect allele	EAF	OR (95% CI)^c	P	Ref.
1p34.3	rs58722170	Serous	C	0.22	1.10 (1.07–1.13)	1.4E−09	25
2q14.1	rs752590	Mucinous	G	0.21	1.30 (1.21–1.39)	2.2E−12	53
2q31.1	rs711830	Mucinous	A	0.32	1.27 (1.20–1.35)	1.1E−14	53
2q31.1	rs6755777	Serous	T	0.32	1.12 (1.09–1.15)	2.7E−15	28
3q25.31	rs62274041	HGSOC	G	0.05	1.57 (1.48–1.66)	2.1E−57	22
5p15.33	rs10069690	Serous	T	0.26	1.13 (1.09–1.17)	1.5E−12	37
5p15.33	rs7705526	S. borderline	A	0.33	1.38 (1.29–1.48)	5.5E−19	37
8q21.13	rs76837345	HGSOC	G	0.07	1.20 (1.13–1.28)	9.0E−10	26
8q24.21	rs1400482	Serous	G	0.87	1.23 (1.19–1.28)	7.4E−26	28
9p22.2	rs10962692	HGSOC	G	0.80	1.36 (1.30–1.42)	1.4E−47	22
9q34.2	rs8176685	HGSOC	G	0.19	1.15 (1.10–1.19)	5.2E−12	25
10p12.31	rs144962376	Serous	TCCCT	0.31	1.10 (1.06–1.13)	6.6E−09	26
17q12	rs7405776	Serous	G	0.41	1.10 (1.07–1.14)	1.9E−10	35
17q12	rs11651755	Clear cell	C	0.49	0.79 (0.73–0.86)	6.8E−09	35
17q21.31	rs7207826	Serous	C	0.27	1.14 (1.10–1.18)	1.2E−14	36
17q21.32	rs1879586	HGSOC	G	0.18	1.15 (1.10–1.19)	2.5E−12	26
19p13.11	rs4808075	HGSOC	C	0.30	1.20 (1.16–1.24)	3.3E−24	29
19q13.2	rs688187	Mucinous	A	0.31	1.43 (1.33–1.53)	1.2E−22	53
In Han Chinese ancestry populations only
9q22.33	rs1413299	Serous	C	0.40	1.53 (1.25–1.86)	1.9E−08	24
10p11.21	rs1192691	Serous	A	0.36	0.81 (0.70–0.95)	2.6E−08	24

Abbreviations: EAF, effect allele frequency; ref., reference; S. borderline, serous borderline.
↵^aIn European ancestry populations unless otherwise specified.
↵^bAll risk loci listed had BFDP <10%.
↵^cAll ORs, CIs, and P values from the OncoArray meta-analysis (ref. 23).

Table 3.

Previously published EOC risk loci not confirmed by OncoArray meta-analysis at P < 5 × 10⁻⁸ (ref. 23)^{^a^,^b}

Locus	Lead SNP	Phenotype	Effect allele	EAF	OR (95% CI)^c	P	Ref.
1p36.12	rs56318008	All invasive EOC	T	0.15	1.08 (1.04–1.12)	8.4E−05	25
4q26	rs17329882	All invasive EOC	C	0.24	1.08 (1.04–1.11)	2.5E−06	25
4q32.3	rs4691139	BRCA1 mutation+	G	0.47	1.16 (1.09–1.23)	4.3E−07	41
6p22.1	rs6456822	All invasive EOC	T	0.69	1.07 (1.04–1.10)	1.2E−06	25
17q11.2	rs143663961	All invasive EOC	A	0.73	1.08 (1.05–1.11)	1.3E−07	25

Abbreviations: EAF, effect allele frequency; ref., reference; S. borderline, serous borderline.
↵^aIn European ancestry populations.
↵^bAll risk loci listed had BFDP >10%.
↵^cAll ORs, CIs, and P values from the OncoArray meta-analysis (ref. 23).

Table 4.

Pleiotropic cancer risk loci shared between EOC and breast and/or prostate cancers identified at P < 10⁻⁸ specifically by cross-cancer type meta-analysis in European ancestry populations (ref. 40)^a

Locus	Lead SNP	Effect allele, EAF	Cancer type	OR (95% CI)	P
Associations with ovarian, breast, and prostate cancer risk with the same direction of effect
2q13	rs17041869	A	Breast cancer	0.97 (0.94–0.99)	7.1 × 10⁻³
		0.88	Ovarian cancer^b	0.93 (0.88–0.97)	5.3 × 10⁻⁴
			Prostate cancer	0.92 (0.89–0.95)	2.6 × 10⁻⁶
			Meta-analysis	0.94 (0.93–0.96)	5.1 × 10⁻⁹
11q12.3	rs7937840	T	Breast cancer	1.04 (1.02–1.06)	3.6 × 10⁻⁵
		0.26	Ovarian cancer	1.05 (1.01–1.09)	5.8 × 10⁻³
			Prostate cancer	1.05 (1.02–1.08)	8.9 × 10⁻⁴
			Meta-analysis	1.05 (1.03–1.06)	5.0 × 10⁻⁹
19p13.11	rs1469713	A	Breast cancer	0.95 (0.94–0.97)	9.9 × 10⁻⁸
		0.64	Ovarian cancer	0.96 (0.93–0.99)	6.3 × 10⁻³
			Prostate cancer	0.97 (0.94–0.99)	1.0 × 10⁻²
			Meta-analysis	0.96 (0.95–0.97)	3.4 × 10⁻¹⁰
Associations with ovarian and breast cancer risk with the same direction of effect
9q31.1	rs200182588	G	Breast cancer	0.96 (0.94–0.98)	1.9 × 10⁻⁵
		0.56	Ovarian cancer	0.93 (0.89–0.96)	2.8 × 10⁻⁶
			Meta-analysis	0.95 (0.94–0.97)	8.9 × 10⁻⁹
15q26.1	rs8037137	T	Breast cancer	1.07 (1.04–1.10)	1.8 × 10⁻⁷
		0.86	Ovarian cancer	1.09 (1.04–1.14)	2.1 × 10⁻⁴
			Meta-analysis	1.07 (1.05–1.10)	9.1 × 10⁻¹⁰

Abbreviations: EAF, effect allele frequency; ref., reference.
↵^aThis meta-analysis did not include data from the OncoArray project (ref. 23).
↵^bOvarian cancer refers to all invasive EOCs.