A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk

Figures & data

Table I. Distribution of cases and controls, and number of samples with available DNA, in the Nordic – UK case-control study, 2000–2004.

	Glioma	Glioblastoma	Controls
Total subjects with available DNA	728 (%)	329 (%)	1 610 (%)
Total subjects available for SNP analysis	607 (83)	269 (82)	1 286 (80)
Number of Subjects by Country
Sweden	205	100	357
Denmark	110	54	438
UK	206	82	404
Finland	86	33	87
Mean age at diagnosis and age range (years)	47 (19–69)	52 (22–69)	51 (19–69)

Figure 1. Linkage disequilibrium (LD) blocks of the EGFR gene and arrows indicating location of SNPs selected to estimate haplotypes by SAS Genetics. Exons have been redrawn to show the relative positions in the EGFR gene, therefore maps are not to physical scale.

Figure 2. Linkage disequilibrium (LD) blocks of the ERBB2 gene and arrows indicating location of SNPs selected to estimate haplotypes by SAS Genetics. Exons have been redrawn to show the relative positions in the ERBB2 gene, therefore maps are not to physical scale.

Table II. Single nucleotide polymorphisms (SNPs) associated with risk of glioma at the 5% significance level based on trend test, and their heterozygote and homozygote odds ratios, per-allele odds ratios, confidence intervals, and false-positive probabilities.

GENE	SNP, alleles	MG	MGFcontrols	MGFcases	ORhet	ORhom	ORtrend	Ptrend-value	FPRP	Position and putative SNP function
EGFR	rs7809394C/T	TT	0.03	0.04	1.20 (0.99–1.47)	1.32 (0.84–2.08)	1.18 (1.01–1.38)	0.040	0.480	Intron 1
EGFR	rs10225877A/T	TT	0.04	0.05	1.23 (1.01–1.50)	1.28 (0.82–2.01)	1.19 (1.02–1.39)	0.031	0.337	Intron 1
EGFR	rs917881A/G	AA	0.04	0.03	0.78 (0.63–0.96)	0.79 (0.48–1.31)	0.82 (0.69–0.97)	0.020	0.270	Intron 1
EGFR	rs4947979A/G	GG	0.05	0.03	0.74 (0.60–0.90)	0.67 (0.42–1.07)	0.77 (0.65–0.91)	0.002	0.038	Intron 1
EGFR	rs4947983A/C	CC	0.03	0.02	0.78 (0.63–0.96)	0.79 (0.45–1.40)	0.81 (0.68–0.97)	0.023	0.283	Intron 1
EGFR	rs730437A/C	AA	0.23	0.27	1.05 (0.84–1.30)	1.32 (1.03–1.68)	1.15 (1.01–1.30)	0.032	0.314	Intron 4
EGFR	rs11506105A/G	AA	0.18	0.22	1.13 (0.92–1.39)	1.39 (1.08–1.78)	1.17 (1.04–1.33)	0.012	0.227	Intron/exon boundary (6–63)
EGFR	rs4947986A/G	AA	0.07	0.10	1.08 (0.90–1.31)	1.45 (1.05–2.01)	1.15 (1.01–1.32)	0.044	0.458	Intron/exon boundary (7–50)
EGFR	rs3752651C/T	CC	0.03	0.04	1.29 (1.06–1.56)	1.35 (0.85–2.15)	1.24 (1.06–1.45)	0.008	0.112	Intron 13
EGFR	rs1468727C/T	TT	0.07	0.04	0.88 (0.73–1.06)	0.61 (0.40–0.93)	0.83 (0.72–0.97)	0.017	0.256	Intron 13
EGFR	rs10228436A/G	AA	0.12	0.08	0.89 (0.74–1.08)	0.62 (0.45–0.86)	0.83 (0.72–0.95)	0.008	0.110	Intron 15
EGFR	rs845552A/G	GG	0.25	0.21	0.82 (0.66–1.01)	0.72 (0.56–0.92)	0.84 (0.74–0.96)	0.009	0.159	Intron 19
EGFR	rs9642393C/T	CC	0.09	0.06	0.89 (0.74–1.08)	0.67 (0.47–0.97)	0.85 (0.74–0.99)	0.031	0.398	Intron 19

MG, minor genotype; MGF, minor genotype frequency; OR_het, odds ratio of heterozygote versus common homozygote genotypes; OR_hom, odds ratio of rare homozygote versus common homozygote genotypes; FPRP, False-positive report probability based on OR_trend (assuming prior probability of 0.1 and power to detect an OR of 1.3).

Table III. Single nucleotide polymorphisms (SNPs) associated with risk of glioblastoma at the 5% significance level based on trend test, and their heterozygote and homozygote odds ratios, per-allele odds ratios, confidence intervals, and false-positive probabilities.

GENE	SNP, alleles	MG	MGFcontrols	MGFcases	ORhet	ORhom	ORtrend	Ptrend-value	FPRP	Position and putative SNP function
EGFR	rs759171A/C	AA	0.01	0.01	0.71 (0.52–0.98)	0.45 (0.10–1.94)	0.70 (0.52–0.95)	0.020	0.284	Promoter
EGFR	rs17172430A/G	AA	0.007	0.02	0.58 (0.42–0.83)	2.07 (0.71–6.01)	0.70 (0.52–0.96)	0.025	0.326	Intron 1
EGFR	rs17172432C/T	CC	0.04	0.04	0.64 (0.48–0.85)	1.00 (0.54–1.86)	0.76 (0.60–0.96)	0.021	0.277	Intron 1
EGFR	rs17172433A/G	AA	0.02	0.02	0.65 (0.48–0.89)	1.30 (0.55–3.05)	0.76 (0.58–0.99)	0.046	0.430	Intron 1
EGFR	rs4947492A/G	GG	0.20	0.14	1.01 (0.77–1.31)	0.61 (0.42–0.89)	0.82 (0.69–0.98)	0.028	0.344	Intron 1
EGFR	rs12718945G/T	TT	0.21	0.14	0.99 (0.76–1.30)	0.62 (0.42–0.91)	0.83 (0.69–0.98)	0.032	0.334	Intron 1
EGFR	rs4947979A/G	GG	0.05	0.04	0.66 (0.49–0.87)	0.82 (0.46–1.49)	0.75 (0.60–0.94)	0.014	0.184	Intron 1
EGFR	rs11506105A/G	AA	0.18	0.23	1.13 (0.85–1.49)	1.45 (1.03–2.03)	1.20 (1.01–1.42)	0.039	0.378	Intron/exon boundary (6–63)
EGFR	rs11770531C/T	TT	0.01	0.006	0.72 (0.52–1.02)	0.58 (0.13–2.55)	0.73 (0.53–1.00)	0.049	0.474	Intron 6
EGFR	rs4947986A/G	AA	0.07	0.11	1.11 (0.86–1.44)	1.67 (1.10–2.55)	1.22 (1.01–1.47)	0.035	0.397	Intron/exon boundary (7–50)
EGFR	rs9642393C/T	CC	0.09	0.06	0.84 (0.65–1.08)	0.63 (0.38–1.04)	0.81 (0.67–0.99)	0.041	0.416	Intron 19
ERBB2	rs1476278A/G	GG	0.09	0.15	1.06 (0.81–1.37)	1.81 (1.25–2.62)	1.26 (1.05–1.50)	0.011	0.144	Promoter
ERBB2	rs9303274C/T	TT	0.09	0.15	1.04 (0.80–1.36)	1.76 (1.20–2.56)	1.24 (1.03–1.48)	0.021	0.236	Promoter
ERBB2	rs903501A/G	AA	0.08	0.14	1.01 (0.78–1.31)	1.77 (1.20–2.61)	1.22 (1.02–1.46)	0.032	0.351	Promoter
ERBB2	rs2952155C/T	TT	0.05	0.08	1.22 (0.94–1.58)	1.79 (1.11–2.86)	1.28 (1.06–1.56)	0.012	0.206	Intron 4
ERBB2	rs1058808C/G	CC	0.09	0.14	1.21 (0.93–1.58)	1.71 (1.16–2.51)	1.28 (1.07–1.53)	0.007	0.107	Coding sequence, exon 30, non-syn (Pro-Ala)
VEGFR2	rs3828550C/T	TT	0.10	0.15	1.06 (0.81–1.38)	1.60 (1.10–2.35)	1.21 (1.01–1.45)	0.040	0.412	Intron 9

MG, minor genotype; MGF, minor genotype frequency; OR_het, odds ratio of heterozygote versus common homozygote genotypes; OR_hom, odds ratio of rare homozygote versus common homozygote genotypes; FPRP, False-positive report probability based on OR_trend (assuming prior probability of 0.1 and power to detect an OR of 1.3).

Table IV. Associations between EGFR haplotypes and risk of glioblastoma in Denmark, Finland, Sweden, and UK.

EGFR(H)*	Haplotype probabilities		Odds ratio (OR): (95% CI)
	Cases (n=292)	Controls (n=1418)
H1	0.04	0.06	0.44 (0.17, 1.18)
H2	0.49	0.42	1.67 (1.14, 2.45)

*Haplotypes with frequency ≥ 0.05 in cases and/or controls (rs17172430, rs17172432, rs17172433, rs4947492, rs12718945, rs4947979). H1=a-c-a-a-g-a; H2=g-t-g-a-g-a.

Table V. Associations between ERBB2 haplotypes and risk of glioblastoma in Denmark, Finland, Sweden, and UK.

ERBB2(H)*	Haplotype probabilities:		Odds ratio (OR): (95% CI)
	Cases (n=303)	Controls (n=1519)
H1	0.66	0.70	0.61 (0.42, 0.89)
H2	0.33	0.29	1.55 (1.06, 2.27)

*Haplotypes with frequency ≥ 0.05 in cases and/or controls (rs1476278, rs9303274, rs903501). H1=a-c-g; H2=g-t-a.