Several genome-wide searches for common cancers have lead to the identification of a small number of loci that harbor low-risk cancer susceptibility markers. One marker, rs6983267 on chromosome 8q24, has been linked to both colon and prostate cancer, and is therefore a good candidate for a multicancer susceptibility marker. To determine the range of cancer sites associated with rs6983267, we genotyped 7,665 cases of cancer, representing 11 common cancer sites, and 1,910 controls. A significant odds ratio (OR) was observed for prostate cancer for carriers of genotype GG [OR, 1.77; 95% confidence interval (CI), 1.47–2.13]. The homozygote OR was higher for tumors with Gleason score 8 to 10 (OR, 1.94; 95% CI, 1.18–3.20) than for tumors with Gleason score 7 and below (OR, 1.65; 95% CI, 1.31–2.08). Significantly elevated (homozygote) ORs were observed for 4 other cancer sites, including colon (OR, 1.36; 95% CI, 1.08–1.72), kidney (OR, 1.52; 95% CI, 1.12–2.05), thyroid (OR, 1.37; 95% CI, 1.02–1.82), and larynx (OR, 1.39; 95% CI, 1.02–1.90). Information was available on family histories of cancer for eight sites. For six of the eight sites (prostate, breast, bladder, larynx, lung, and kidney), the homozygote ORs were higher for cases with a positive family history (at least one first-degree with any cancer) than for cases with unaffected first-degree relatives. Our results suggest that the range of cancers associated with the rs6983267 marker might be larger than previously thought. [Cancer Res 2008;68(23):9982–6]

In the past year, the results of several genome-wide searches for loci for cancer susceptibility for breast, colon, and prostate cancer have been reported. Several chromosomal regions of interest have been identified, including loci for prostate cancer on chromosomes 2, 3, 6, 7, 8, 10, 11, 17, 19, and X; for colorectal cancer on chromosomes 8, 10, 11, 15, and 18; and for breast cancer on chromosomes 5, 6, 8, 10, and 16 (117). For most of these loci, the effects of the risk alleles seem to be site specific (i.e., different loci were associated with different cancers). However, one region at 8q24, recognized by the marker rs6983267, was associated with both prostate and colon cancer (613). A modest association [odds ratio (OR), 1.2; 95% confidence interval (CI), 1.0–1.43] of rs6983267 was reported in colorectal cancer patients with a positive family history of any malignancy (14), suggesting the possible involvement of the marker in multisite cancer susceptibility. To better characterize the range of cancers associated with the rs6983267 marker on chromosome 8q24, we genotyped 7,665 cases of cancer and 1,910 controls in the Polish population. Poland is well-suited for association studies because of relative genetic homogeneity; for example, Polish founder mutations have been identified for BRCA1, NBS1, and CHEK2 (1820).

Patients. We included patients with 11 of the most common types of cancer in Poland. Together, these sites represent ∼70% of all malignancies diagnosed annually in the country. Study subjects were unselected for age and family history. Patient acceptance rates exceeded 70% for each cancer site. Patients provided written informed consent. The cancer cases for 10 cancer sites were collected from hospitals in Szczecin (Poland) between 1995 and 2007. Prostate cancer cases were collected in Szczecin (n = 704) and in other Polish cities (n = 1,181) between 1999 and 2007 (21). In total, 7,665 cases of cancer were collected, including 1,885 cases of prostate cancer (mean age, 67.4 y; age range, 41–90 y), 1,006 cases of breast cancer (mean age, 56.4 y; age range, 25–88 y), 618 cases of ovarian cancer (mean age, 54.4 y; age range, 16–86 y), 779 cases of colon cancer (mean age, 63.4 y; age range, 23–96 y), 465 cases of kidney cancer (mean age, 57.5 y; age range, 17–85 y), 303 cases of bladder cancer (mean age, 62.6 y; age range, 25–88 y), 400 cases of laryngeal cancer (mean age, 48.4 y; age range, 12–79 y), 738 cases of lung cancer (mean age, 61.4 y; age range, 29–88 y), 498 cases of malignant melanoma (mean age, 53.4 y; age range, 25–85), 488 cases of stomach cancer (mean age, 58.5 y; age range, 25–83 y), and 485 cases of thyroid cancer (mean age, 48.4 y; age range, 12–79 y).

Information was available on family histories of cancer for eight sites [prostate, breast, colon, bladder, larynx, lung, skin (malignant melanoma), and kidney]. For one site (stomach), information was available only on family history of cancer at the same site. A positive family history was defined in two ways: first, at least one first-degree relative affected by cancer at any site and, second, a first-degree relative with cancer in the same site. The study was approved by the ethics committee of the Pomeranian Medical University.

Controls. Two nonoverlapping control groups were used. The first control group consisted of 946 healthy adults, including 510 women (age range, 25–91 y; mean 62.9) and 436 men (age range, 34–90 y; mean 64.3). These controls were selected at random from the computerized patient lists of five large family practices located in the region of Szczecin. These healthy adults participated in 2003 and 2004. Participation rates for this group exceeded 70%. A detailed family history of cancer was taken (612 of the 946 adults reported a negative family history of cancer in all first-degree relatives). Study subjects were included regardless of their cancer family history. Individuals affected with any malignancy were excluded from the study. The second source of controls consisted of 964 healthy adults: 509 women (age range, 25–88 y; mean, 56.0) and 455 men (age range, 23–87 y; mean, 61.6) who were part of a population-based study of 1.5 million residents of West Pomerania, designed to identify familial aggregations of cancer. The controls were selected at random from a registry of patients who participated in the population-based study. These subjects were invited for an interview in 2007. A detailed family history of cancer was taken. Individuals affected with any malignancy, or with a first-degree relative diagnosed with cancer were excluded from this control group. In total, there were 1,910 cancer-free controls (1,576 of the 1,910 controls reported a negative family history of cancer in all first-degree relatives). The genotypes for the rs6983267 marker were compared for the controls by age, by sex, and by source. Because there were no observed differences between the allele frequencies in the controls from the two sources, by sex or by age, all controls were combined into a single group to generate the most precise estimate of the rs6983267 genotype frequencies in the underlying general population (Table 1).

Table 1.

Frequency of rs6983267 in controls, by source, by age, and by sex

Control groupAlleles no (%)Genotypes no (%)
All controls T 2003 (52.4%) TT 513 (27.0%) 
n = 1,910 G 1817 (47.6%) GT 977 (51.0%) 
  GG 420 (22.0%) 
Control group 1 T 1007 (53.2%) TT 261 (27.6%) 
Family doctor series G 885 (46.8%) GT 485 (51.3%) 
n = 946  GG 200 (21.1%) 
Control group 2 T 996 (51.6%) TT 252 (26.0%) 
Population-based series G 932 (48.4%) GT 492 (51.0%) 
n = 964  GG 220 (23.0%) 
Males T 930 (52.2%) TT 234 (26.2%) 
n = 891 G 852 (47.8%) GT 462 (52.2%) 
  GG 195 (22.0%) 
Females T 1073 (52.6%) TT 279 (27.5%) 
n = 1,019 G 965 (47.4%) GT 515 (50.5%) 
  GG 225 (22.0%) 
Age, <60 y T 948 (51.5%) TT 239 (26.0%) 
n = 921 G 894 (48.5%) GT 470 (51.0%) 
  GG 212 (23.0%) 
Age, ≥60 y T 1055 (53.3%) TT 274 (28.0%) 
n = 989 G 923 (46.7%) GT 507 (51.0%) 
  GG 208 (21.0%) 
Control groupAlleles no (%)Genotypes no (%)
All controls T 2003 (52.4%) TT 513 (27.0%) 
n = 1,910 G 1817 (47.6%) GT 977 (51.0%) 
  GG 420 (22.0%) 
Control group 1 T 1007 (53.2%) TT 261 (27.6%) 
Family doctor series G 885 (46.8%) GT 485 (51.3%) 
n = 946  GG 200 (21.1%) 
Control group 2 T 996 (51.6%) TT 252 (26.0%) 
Population-based series G 932 (48.4%) GT 492 (51.0%) 
n = 964  GG 220 (23.0%) 
Males T 930 (52.2%) TT 234 (26.2%) 
n = 891 G 852 (47.8%) GT 462 (52.2%) 
  GG 195 (22.0%) 
Females T 1073 (52.6%) TT 279 (27.5%) 
n = 1,019 G 965 (47.4%) GT 515 (50.5%) 
  GG 225 (22.0%) 
Age, <60 y T 948 (51.5%) TT 239 (26.0%) 
n = 921 G 894 (48.5%) GT 470 (51.0%) 
  GG 212 (23.0%) 
Age, ≥60 y T 1055 (53.3%) TT 274 (28.0%) 
n = 989 G 923 (46.7%) GT 507 (51.0%) 
  GG 208 (21.0%) 

Genotyping. DNA was isolated from 5 to 10 cc peripheral blood. The rs6983267 variant was analyzed by RFLP-PCR using primers F: 5′-CTG AAC TGT GGG GTT GGC TGT CA-3′ and R: 5"-TAA TAC CCT CAT CGT CCT TTG AG-3′, and the NmuCI enzyme. The test was validated by sequencing of 88 randomly selected samples, and the results of RFLP-PCR and sequencing were 100% concordant. In addition, 589 randomly selected samples were reevaluated by RFLP-PCR, and the results were 99.5% concordant.

Statistical analysis. The prevalence of each of the alleles was measured in cases and controls. ORs were generated from two-by-two contingency tables and their statistical significance was assessed using Fisher exact test. We considered P values below 0.05 to indicate statistical significance. The P values have not been corrected for multiple testing.

We genotyped 7,665 cases and 1,910 controls for the rs6983267 variant. The ORs associated with this single nucleotide polymorphism (SNP) for each of the 11 cancer sites are presented in Table 2. Significant ORs were seen in association with allele G (1 or 2 copies) for 5 cancer sites, including prostate (OR, 1.43; P = 10−9), colon (OR, 1.13; P = 0.01), kidney (OR, 1.43; P = 0.007), thyroid (OR, 1.27; P = 0.04), and larynx (OR, 1.23; P = 0.04). The ORs for four other sites [breast, stomach, lung, and skin (malignant melanoma)] were greater than unity but were nonsignificant. For all sites, except stomach, the homozygote ORs were higher than the heterozygote ORs (Table 2).

Table 2.

Association between rs6983267 genotypes and cancer risk, by cancer site

SiteAlleles no (%)OR* (95% CI)*PGenotype no (%)OR (95% CI)P
Prostate T 1712 (45.4%) Reference  TT 385 (20.4%) Reference  
n = 1,885 G 2058 (54.6%) 1.43 (1.23–1.66) 10−9 GT 942 (50.0%) 1.28 (1.09–1.51) 0.002 
    GG 558 (29.6%) 1.77 (1.47–2.13) 10−9 
Aggressive prostate cancer T 136 (44.7%) Reference  TT 27 (17.7%) Reference  
n = 152 G 168 (55.3%) 1.71 (1.11–2.63) 0.01 GT 82 (53.9%) 1.59 (1.02–2.50) 0.04 
    GG 43 (28.3%) 1.94 (1.18–3.20) 0.009 
Nonaggressive prostate cancer T 776 (46.1%) Reference  TT 183 (21.8%) Reference  
n = 841 G 906 (53.9%) 1.32 (1.09–1.60) <0.0001 GT 410 (48.7%) 1.18 (0.96–1.44) 0.1 
    GG 248 (29.5%) 1.65 (1.31–2.08) <0.0001 
Breast T 1015 (50.4%) Reference  TT 254 (25.2%) Reference  
n = 1,006 G 997 (49.6%) 1.09 (0.91–1.29) 0.1 GT 507 (50.4%) 1.09 (0.91–1.29) 0.6 
    GG 245 (24.4%) 1.18 (0.95–1.46) 0.1 
Ovary T 615 (49.7%) Reference  TT 166 (26.8%) Reference  
n = 618 G 621 (50.3%) 1.00 (0.81–1.23) 0.1 GT 283 (45.8%) 0.89 (0.72–1.12) 0.3 
    GG 169 (27.4%) 1.24 (0.97–1.60) 0.1 
Colon T 757 (48.6%) Reference  TT 191 (24.5%) Reference  
n = 779 G 801 (51.4%) 1.13 (0.93–1.37) 0.01 GT 375 (48.0%) 1.03 (0.84–1.26) 0.8 
    GG 213 (27.5%) 1.36 (1.08–1.72) 0.01 
Kidney T 442 (47.5%) Reference  TT 95 (20.4%) Reference  
n = 465 G 488 (52.5%) 1.43 (1.12–1.83) 0.007 GT 252 (54.2%) 1.39 (1.07–1.80) 0.01 
    GG 118 (25.4%) 1.52 (1.12–2.05) 0.008 
Bladder T 311 (51.3%) Reference  TT 82 (27.0%) Reference  
n = 303 G 295 (48.7%) 1.00 (0.75–1.30) 0.6 GT 147 (48.5%) 0.94 (0.70–1.26) 0.5 
    GG 74 (24.5%) 1.10 (0.76–1.51) 0.7 
Larynx T 387 (48.3%) Reference  TT 92 (23.0%) Reference  
n = 400 G 413 (51.7%) 1.23 (0.95–1.58) 0.04 GT 203 (50.7%) 1.16 (0.89–1.52) 0.3 
    GG 105 (26.3%) 1.39 (1.02–1.90) 0.04 
Lung T 741 (50.2%) Reference  TT 181 (24.5%) Reference  
n = 738 G 735 (49.8%) 1.13 (0.93–1.37) 0.1 GT 379 (51.3%) 1.10 (0.89–1.35) 0.4 
    GG 178 (24.1%) 1.29 (0.94–1.5) 0.1 
Melanoma T 497 (49.9%) Reference  TT 123 (24.7%) Reference  
n = 498 G 499 (50.1%) 1.12 (0.89–1.41) 0.1 GT 251 (50.4%) 1.07 (0.84–1.36) 0.6 
    GG 124 (24.9%) 1.23 (0.93–1.63) 0.1 
Stomach T 507 (51.9%) Reference  TT 126 (25.8%) Reference  
n = 488 G 469 (48.1%) 1.05 (0.84–1.32) 0.8 GT 255 (52.2%) 1.06 (0.84–1.35) 0.6 
    GG 107 (22.0%) 1.04 (0.78–1.38) 0.8 
Thyroid T 472 (48.6%) Reference  TT 109 (22.5%) Reference  
n = 485 G 498 (51.4%) 1.27 (1.00–1.60) 0.04 GT 254 (52.5%) 1.22 (0.95–1.57) 0.1 
    GG 122 (25.0%) 1.37 (1.02–1.82) 0.04 
Controls T 2003 (52.4%) − (−) − TT 513 (27.0%) − (−) − 
n = 1,910 G 1817 (47.6%)   GT 977 (51.0%)   
    GG 420 (22.0%)   
SiteAlleles no (%)OR* (95% CI)*PGenotype no (%)OR (95% CI)P
Prostate T 1712 (45.4%) Reference  TT 385 (20.4%) Reference  
n = 1,885 G 2058 (54.6%) 1.43 (1.23–1.66) 10−9 GT 942 (50.0%) 1.28 (1.09–1.51) 0.002 
    GG 558 (29.6%) 1.77 (1.47–2.13) 10−9 
Aggressive prostate cancer T 136 (44.7%) Reference  TT 27 (17.7%) Reference  
n = 152 G 168 (55.3%) 1.71 (1.11–2.63) 0.01 GT 82 (53.9%) 1.59 (1.02–2.50) 0.04 
    GG 43 (28.3%) 1.94 (1.18–3.20) 0.009 
Nonaggressive prostate cancer T 776 (46.1%) Reference  TT 183 (21.8%) Reference  
n = 841 G 906 (53.9%) 1.32 (1.09–1.60) <0.0001 GT 410 (48.7%) 1.18 (0.96–1.44) 0.1 
    GG 248 (29.5%) 1.65 (1.31–2.08) <0.0001 
Breast T 1015 (50.4%) Reference  TT 254 (25.2%) Reference  
n = 1,006 G 997 (49.6%) 1.09 (0.91–1.29) 0.1 GT 507 (50.4%) 1.09 (0.91–1.29) 0.6 
    GG 245 (24.4%) 1.18 (0.95–1.46) 0.1 
Ovary T 615 (49.7%) Reference  TT 166 (26.8%) Reference  
n = 618 G 621 (50.3%) 1.00 (0.81–1.23) 0.1 GT 283 (45.8%) 0.89 (0.72–1.12) 0.3 
    GG 169 (27.4%) 1.24 (0.97–1.60) 0.1 
Colon T 757 (48.6%) Reference  TT 191 (24.5%) Reference  
n = 779 G 801 (51.4%) 1.13 (0.93–1.37) 0.01 GT 375 (48.0%) 1.03 (0.84–1.26) 0.8 
    GG 213 (27.5%) 1.36 (1.08–1.72) 0.01 
Kidney T 442 (47.5%) Reference  TT 95 (20.4%) Reference  
n = 465 G 488 (52.5%) 1.43 (1.12–1.83) 0.007 GT 252 (54.2%) 1.39 (1.07–1.80) 0.01 
    GG 118 (25.4%) 1.52 (1.12–2.05) 0.008 
Bladder T 311 (51.3%) Reference  TT 82 (27.0%) Reference  
n = 303 G 295 (48.7%) 1.00 (0.75–1.30) 0.6 GT 147 (48.5%) 0.94 (0.70–1.26) 0.5 
    GG 74 (24.5%) 1.10 (0.76–1.51) 0.7 
Larynx T 387 (48.3%) Reference  TT 92 (23.0%) Reference  
n = 400 G 413 (51.7%) 1.23 (0.95–1.58) 0.04 GT 203 (50.7%) 1.16 (0.89–1.52) 0.3 
    GG 105 (26.3%) 1.39 (1.02–1.90) 0.04 
Lung T 741 (50.2%) Reference  TT 181 (24.5%) Reference  
n = 738 G 735 (49.8%) 1.13 (0.93–1.37) 0.1 GT 379 (51.3%) 1.10 (0.89–1.35) 0.4 
    GG 178 (24.1%) 1.29 (0.94–1.5) 0.1 
Melanoma T 497 (49.9%) Reference  TT 123 (24.7%) Reference  
n = 498 G 499 (50.1%) 1.12 (0.89–1.41) 0.1 GT 251 (50.4%) 1.07 (0.84–1.36) 0.6 
    GG 124 (24.9%) 1.23 (0.93–1.63) 0.1 
Stomach T 507 (51.9%) Reference  TT 126 (25.8%) Reference  
n = 488 G 469 (48.1%) 1.05 (0.84–1.32) 0.8 GT 255 (52.2%) 1.06 (0.84–1.35) 0.6 
    GG 107 (22.0%) 1.04 (0.78–1.38) 0.8 
Thyroid T 472 (48.6%) Reference  TT 109 (22.5%) Reference  
n = 485 G 498 (51.4%) 1.27 (1.00–1.60) 0.04 GT 254 (52.5%) 1.22 (0.95–1.57) 0.1 
    GG 122 (25.0%) 1.37 (1.02–1.82) 0.04 
Controls T 2003 (52.4%) − (−) − TT 513 (27.0%) − (−) − 
n = 1,910 G 1817 (47.6%)   GT 977 (51.0%)   
    GG 420 (22.0%)   
*

OR for allele G.

OR for particular genotype using TT genotype as a reference.

Aggressive prostate cancer, Gleason 8–10; nonaggressive prostate cancer, Gleason <8.

We investigated how a family history of any cancer affected the observed ORs. Family history of cancer was available for eight sites. For six sites [prostate, breast, bladder, larynx, lung, and skin (malignant melanoma)], the homozygote ORs were higher for cases with an affected first-degree relative than for cases with unaffected first-degree relatives (Table 3). For five of these six sites, the heterozygote ORs were also greater for familial cases than for nonfamilial cases. The differences were highest for smoking-related cancers (bladder, laryngeal, and lung cancer). For these three cancers, the homozygote ORs were between 1.44 and 1.89 for familial cases, and between 0.86 and 1.13 for nonfamilial cases; the heterozygote ORs ranged from 1.13 to 1.62 for familial cases, compared with 0.85 to 0.93 for nonfamilial cases.

Table 3.

Association between rs6983267 and cancer site, by family history of any cancer

SiteGenotype no (%)OR (95% CI)PGenotype no (%)OR (95% CI)PP for difference*
 At least one first-degree relative affected by cancer at any site   All first-degree relatives unaffected by any cancer    
Prostate TT 157 (19.4%) Reference  TT 227 (21.1%) Reference   
n = 1,883 GT 416 (51.4%) 1.39 (1.12–1.73) 0.003 GT 525 (48.9%) 1.21 (0.99–1.47) 0.05 0.4 
 GG 236 (29.2%) 1.82 (1.42–2.33) <0.0001 GG 322 (30.0%) 1.71 (1.37–2.14) <0.0001  
Breast TT 120 (24.5%) Reference  TT 134 (25.9%) Reference   
n = 1,006 GT 251 (51.3%) 1.09 (0.86–1.40) 0.5 GT 256 (49.5%) 1.00 (0.79–1.27) 1.0 0.7 
 GG 118 (24.1%) 1.20 (0.89–1.55) 0.3 GG 127 (24.6%) 1.15 (0.86–1.52) 0.3  
Colon TT 71 (24.7%) Reference  TT 120 (24.4%) Reference   
n = 779 GT 148 (51.6%) 1.10 (0.80–1.48) 0.6 GT 227 (46.1%) 0.99 (0.77–1.27) 1.0 0.9 
 GG 68 (23.7%) 1.16 (0.81–1.66) 0.4 GG 145 (29.5%) 1.46 (1.10–1.93) 0.008  
Bladder TT 26 (22.4%) Reference  TT 56 (29.9%) Reference   
n = 303 GT 56 (48.3%) 1.13 (0.70–1.82) 0.7 GT 91 (48.7%) 0.85 (0.60–1.21) 0.4 0.2 
 GG 34 (29.3%) 1.58 (0.93–2.69) 0.1 GG 40 (21.4%) 0.86 (0.56–1.32) 0.5  
Larynx TT 30 (17.6%) Reference  TT 62 (27.0%) Reference   
n = 400 GT 93 (54.7%) 1.62 (1.06–2.49) 0.03 GT 110 (47.8%) 0.93 (0.67–1.30) 0.7 0.03 
 GG 47 (27.6%) 1.89 (1.17–3.06) 0.008 GG 58 (25.2%) 1.13 (0.77–1.66) 0.5  
Lung TT 63 (21.5%) Reference  TT 108 (28.1%) Reference   
n = 677 GT 155 (52.9%) 1.29 (0.94–1.77) 0.1 GT 188 (49.0%) 0.91 (0.70–1.19) 0.5 0.05 
 GG 75 (25.6%) 1.44 (1.00–2.07) 0.05 GG 88 (22.9%) 0.98 (0.72–1.35) 0.9  
Melanoma TT 56 (25.6%) Reference  TT 62 (24.9%) Reference   
n = 468 GT 114 (52.0%) 1.07 (0.76–1.50) 0.7 GT 127 (51.0%) 1.07 (0.77–1.49) 0.7 0.9 
 GG 49 (22.4%) 1.06 (0.70–1.59) 0.8 GG 60 (24.1%) 1.17 (0.79–1.71) 0.4  
Kidney TT 29 (21.2%) Reference  TT 35 (21.5%) Reference   
n = 300 GT 68 (49.6%) 1.23 (0.78–1.93) 0.4 GT 82 (50.3%) 1.23 (0.81–1.86) 0.3 1.0 
 GG 40 (29.2%) 1.67 (1.01–2.75) 0.04 GG 46 (28.2%) 1.59 (1.00–2.52) 0.06  
Controls TT 422 (26.8%) − (−) − TT 422 (26.8%) − (−) −  
n = 1,576 GT 805 (51.1%)   GT 805 (51.1%)    
 GG 349 (22.1%)   GG 349 (22.1%)    
SiteGenotype no (%)OR (95% CI)PGenotype no (%)OR (95% CI)PP for difference*
 At least one first-degree relative affected by cancer at any site   All first-degree relatives unaffected by any cancer    
Prostate TT 157 (19.4%) Reference  TT 227 (21.1%) Reference   
n = 1,883 GT 416 (51.4%) 1.39 (1.12–1.73) 0.003 GT 525 (48.9%) 1.21 (0.99–1.47) 0.05 0.4 
 GG 236 (29.2%) 1.82 (1.42–2.33) <0.0001 GG 322 (30.0%) 1.71 (1.37–2.14) <0.0001  
Breast TT 120 (24.5%) Reference  TT 134 (25.9%) Reference   
n = 1,006 GT 251 (51.3%) 1.09 (0.86–1.40) 0.5 GT 256 (49.5%) 1.00 (0.79–1.27) 1.0 0.7 
 GG 118 (24.1%) 1.20 (0.89–1.55) 0.3 GG 127 (24.6%) 1.15 (0.86–1.52) 0.3  
Colon TT 71 (24.7%) Reference  TT 120 (24.4%) Reference   
n = 779 GT 148 (51.6%) 1.10 (0.80–1.48) 0.6 GT 227 (46.1%) 0.99 (0.77–1.27) 1.0 0.9 
 GG 68 (23.7%) 1.16 (0.81–1.66) 0.4 GG 145 (29.5%) 1.46 (1.10–1.93) 0.008  
Bladder TT 26 (22.4%) Reference  TT 56 (29.9%) Reference   
n = 303 GT 56 (48.3%) 1.13 (0.70–1.82) 0.7 GT 91 (48.7%) 0.85 (0.60–1.21) 0.4 0.2 
 GG 34 (29.3%) 1.58 (0.93–2.69) 0.1 GG 40 (21.4%) 0.86 (0.56–1.32) 0.5  
Larynx TT 30 (17.6%) Reference  TT 62 (27.0%) Reference   
n = 400 GT 93 (54.7%) 1.62 (1.06–2.49) 0.03 GT 110 (47.8%) 0.93 (0.67–1.30) 0.7 0.03 
 GG 47 (27.6%) 1.89 (1.17–3.06) 0.008 GG 58 (25.2%) 1.13 (0.77–1.66) 0.5  
Lung TT 63 (21.5%) Reference  TT 108 (28.1%) Reference   
n = 677 GT 155 (52.9%) 1.29 (0.94–1.77) 0.1 GT 188 (49.0%) 0.91 (0.70–1.19) 0.5 0.05 
 GG 75 (25.6%) 1.44 (1.00–2.07) 0.05 GG 88 (22.9%) 0.98 (0.72–1.35) 0.9  
Melanoma TT 56 (25.6%) Reference  TT 62 (24.9%) Reference   
n = 468 GT 114 (52.0%) 1.07 (0.76–1.50) 0.7 GT 127 (51.0%) 1.07 (0.77–1.49) 0.7 0.9 
 GG 49 (22.4%) 1.06 (0.70–1.59) 0.8 GG 60 (24.1%) 1.17 (0.79–1.71) 0.4  
Kidney TT 29 (21.2%) Reference  TT 35 (21.5%) Reference   
n = 300 GT 68 (49.6%) 1.23 (0.78–1.93) 0.4 GT 82 (50.3%) 1.23 (0.81–1.86) 0.3 1.0 
 GG 40 (29.2%) 1.67 (1.01–2.75) 0.04 GG 46 (28.2%) 1.59 (1.00–2.52) 0.06  
Controls TT 422 (26.8%) − (−) − TT 422 (26.8%) − (−) −  
n = 1,576 GT 805 (51.1%)   GT 805 (51.1%)    
 GG 349 (22.1%)   GG 349 (22.1%)    

NOTE: In this case, a positive family history is defined as at least one first-degree relative affected by cancer at any site. Family history information of cancer at various sites was not available for ovarian, thyroid, and stomach cancer.

*

P value for difference in the frequency of the GG and GT genotype between familial cases and nonfamilial cases.

Controls with a negative family history of cancer in all first-degree relatives.

We also investigated how the ORs are influenced by a family history of cancer at the same site (Table 4). The was no statistical difference in the ORs for familial cases versus nonfamilial cases for any of the studied sites (all P values for difference ≥0.1). For prostate cancer, the homozygote and the heterozygote ORs were higher for familial cases (2.04 and 1.63, respectively) than for nonfamilial cases (1.75 and 1.25, respectively), but the differences were not statistically significant. A similar (nonsignificant) trend was seen for breast cancer.

Table 4.

Association between rs6983267 and cancer site, by family history of cancer at the same site

SiteGenotype no (%)OR (95% CI)PGenotype no (%)OR (95% CI)P
 At least one first degree relative affected by cancer at the same site   All first degree relatives unaffected by cancer at the same site   
Prostate TT 36 (17.3%) Reference  TT 348 (20.8%) Reference  
n = 1,883 GT 112 (53.9%) 1.63 (1.10–2.42) 0.01 GT 829 (49.5%) 1.25 (1.06–1.47) 0.009 
 GG 60 (28.8%) 2.04 (1.32–3.14) 0.001 GG 498 (29.7%) 1.75 (1.45–2.11) <0.0001 
Breast TT 26 (23.6%) Reference  TT 228 (25.4%) Reference  
n = 1,006 GT 55 (50.0%) 1.11 (0.69–1.79) 0.7 GT 452 (50.4%) 1.04 (0.86–1.26) 0.7 
 GG 29 (23.4%) 1.36 (0.79–2.35) 0.3 GG 216 (24.2%) 1.16 (0.92–1.45) 0.2 
Colon TT 23 (32.4%) Reference  TT 168 (23.7%) Reference  
n = 779 GT 33 (46.5%) 0.75 (0.44–1.30) 0.3 GT 342 (48.3%) 1.07 (0.86–1.32) 0.5 
 GG 15 (21.1%) 0.80 (0.41–1.55) 0.6 GG 198 (28.0%) 1.44 (1.13–1.83) 0.004 
Bladder TT 4 (19.0%) Reference  TT 78 (27.6%) Reference  
n = 303 GT 11 (52.4%) 1.44 (0.46–4.56) 0.6 GT 136 (48.2%) 0.91 (0.68–1.23) 0.6 
 GG 6 (28.6%) 1.83 (0.51–6.54) 0.4 GG 68 (24.2%) 1.06 (0.75–1.51) 0.7 
Larynx TT 6 (28.6%) Reference  TT 86 (22.7%) Reference  
n = 400 GT 11 (53.4%) 1.00 (0.35–2.62) 1.0 GT 192 (50.7%) 1.17 (0.89–1.54) 0.3 
 GG 4 (19.0%) 0.81 (0.23–2.90) 1.0 GG 101 (26.6%) 1.43 (1.05–1.66) 0.03 
Lung TT 20 (26.0%) Reference  TT 151 (25.2%) Reference  
n = 677 GT 42 (54.5%) 1.10 (0.64–1.90) 0.8 GT 301 (50.2%) 1.05 (0.84–1.31) 0.7 
 GG 15 (19.5%) 0.91 (0.46–1.81) 0.9 GG 148 (24.6%) 1.20 (0.92–1.55) 0.2 
Melanoma TT 6 (16.7%) Reference  TT 112 (25.9%) Reference  
n = 468 GT 25 (69.4%) 2.19 (0.89–5.37) 0.09 GT 216 (50.0%) 1.01 (0.79–1.30) 0.9 
 GG 5 (13.9%) 1.02 (0.31–3.36) 1.0 GG 104 (24.1%) 1.13 (0.84–1.53) 0.4 
Stomach TT 11 (27.5%) Reference  TT 115 (25.7%) Reference  
n = 488 GT 21 (52.5%) 1.00 (0.50–2.10) 1.0 GT 234 (52.2%) 1.07 (0.83–1.37) 0.6 
 GG 8 (20.0%) 0.90 (0.35–2.23) 1.0 GG 99 (22.1%) 1.05 (0.78–1.42) 0.8 
Controls TT 513 (27.0%) − (−) − TT 513 (27.0%) − (−) − 
n = 1,910 GT 977 (51.0%)   GT 977 (51.0%)   
 GG 420 (22.0%)   GG 420 (22.0%)   
SiteGenotype no (%)OR (95% CI)PGenotype no (%)OR (95% CI)P
 At least one first degree relative affected by cancer at the same site   All first degree relatives unaffected by cancer at the same site   
Prostate TT 36 (17.3%) Reference  TT 348 (20.8%) Reference  
n = 1,883 GT 112 (53.9%) 1.63 (1.10–2.42) 0.01 GT 829 (49.5%) 1.25 (1.06–1.47) 0.009 
 GG 60 (28.8%) 2.04 (1.32–3.14) 0.001 GG 498 (29.7%) 1.75 (1.45–2.11) <0.0001 
Breast TT 26 (23.6%) Reference  TT 228 (25.4%) Reference  
n = 1,006 GT 55 (50.0%) 1.11 (0.69–1.79) 0.7 GT 452 (50.4%) 1.04 (0.86–1.26) 0.7 
 GG 29 (23.4%) 1.36 (0.79–2.35) 0.3 GG 216 (24.2%) 1.16 (0.92–1.45) 0.2 
Colon TT 23 (32.4%) Reference  TT 168 (23.7%) Reference  
n = 779 GT 33 (46.5%) 0.75 (0.44–1.30) 0.3 GT 342 (48.3%) 1.07 (0.86–1.32) 0.5 
 GG 15 (21.1%) 0.80 (0.41–1.55) 0.6 GG 198 (28.0%) 1.44 (1.13–1.83) 0.004 
Bladder TT 4 (19.0%) Reference  TT 78 (27.6%) Reference  
n = 303 GT 11 (52.4%) 1.44 (0.46–4.56) 0.6 GT 136 (48.2%) 0.91 (0.68–1.23) 0.6 
 GG 6 (28.6%) 1.83 (0.51–6.54) 0.4 GG 68 (24.2%) 1.06 (0.75–1.51) 0.7 
Larynx TT 6 (28.6%) Reference  TT 86 (22.7%) Reference  
n = 400 GT 11 (53.4%) 1.00 (0.35–2.62) 1.0 GT 192 (50.7%) 1.17 (0.89–1.54) 0.3 
 GG 4 (19.0%) 0.81 (0.23–2.90) 1.0 GG 101 (26.6%) 1.43 (1.05–1.66) 0.03 
Lung TT 20 (26.0%) Reference  TT 151 (25.2%) Reference  
n = 677 GT 42 (54.5%) 1.10 (0.64–1.90) 0.8 GT 301 (50.2%) 1.05 (0.84–1.31) 0.7 
 GG 15 (19.5%) 0.91 (0.46–1.81) 0.9 GG 148 (24.6%) 1.20 (0.92–1.55) 0.2 
Melanoma TT 6 (16.7%) Reference  TT 112 (25.9%) Reference  
n = 468 GT 25 (69.4%) 2.19 (0.89–5.37) 0.09 GT 216 (50.0%) 1.01 (0.79–1.30) 0.9 
 GG 5 (13.9%) 1.02 (0.31–3.36) 1.0 GG 104 (24.1%) 1.13 (0.84–1.53) 0.4 
Stomach TT 11 (27.5%) Reference  TT 115 (25.7%) Reference  
n = 488 GT 21 (52.5%) 1.00 (0.50–2.10) 1.0 GT 234 (52.2%) 1.07 (0.83–1.37) 0.6 
 GG 8 (20.0%) 0.90 (0.35–2.23) 1.0 GG 99 (22.1%) 1.05 (0.78–1.42) 0.8 
Controls TT 513 (27.0%) − (−) − TT 513 (27.0%) − (−) − 
n = 1,910 GT 977 (51.0%)   GT 977 (51.0%)   
 GG 420 (22.0%)   GG 420 (22.0%)   

NOTE: In this case, a positive family history is defined as a first-degree relative with cancer at the same site. Family history information of cancer at the same site was not available for ovarian and thyroid cancer. There were too few cases of familial kidney cancers (n = 5) to present ORs separately for this familial subgroup.

In a previous study, the association with rs6983267 was stronger for high-grade prostate cancers than for low-grade cancers (22). In our study, Gleason score was available for 993 cases of prostate cancer; the OR associated with the G allele was higher for aggressive tumors (Gleason score 8 or more; OR, 1.71), than for tumors with Gleason score 7 and below (OR, 1.32), but the difference was not statistically significant.

We are able to confirm previous reports that the locus on chromosome 8q24, marked by rs6983267, predisposes to prostate cancer (homozygote OR, 1.8) and to colon cancer (homozygote OR, 1.4). The ORs observed in the Polish population for these cancers are similar to those reported in other ethnic groups (513). We observed similar ORs for cancers of the kidney, thyroid, and larynx (homozygote ORs of 1.5, 1.4, and 1.4, respectively). These associations were marginally significant, possibly due to smaller sample sizes (465, 485, and 400 cases respectively); however, a number of comparisons were made, and it is possible that some positive associations were observed by chance. Although we did not see statistically significant associations for allele G of rs6983267 and other cancer sites [breast, ovary, bladder, stomach, lung, and skin (malignant melanoma)], for these sites, the homozygote ORs were above unity (range, 1.04 to 1.29). In addition, for five sites (prostate, breast, bladder, larynx, and lung), the homozygote and the heterozygote ORs were higher for cases with a family history of any cancer in a first-degree relative than for cases with all first-degree relatives unaffected.

These findings suggest that the locus on chromosome 8q24, marked by rs6983267, is involved in carcinogenesis of several different organs. In a series of 996 patients with colorectal cancer in Finland, a higher frequency of the G allele was seen in colon cancer patients when a positive family history of another type of cancer was present (OR, 1.20; 95% CI, 1–1.43; P = 0.05; ref. 14). Three previous studies reported no association between the G allele of rs6983267 and breast, endometrial cancer, and chronic lymphocytic leukemia (2325). However, each study was too small to rule out a modest effect. Other polymorphisms in this region of 8q24 have been linked to breast cancer (rs13281615, which is localized 58 kb from rs6983267) and testicular germ cell tumors (rs10505476 localized 5 kb from rs6983267; refs. 17, 26).

The frequency of allele G of rs6983267 is reported to be high among all populations, varying from 31% in Native Hawaiians to 85% in African Americans (7). The frequency of this allele in our population is 48%, similar to the frequency reported in other Caucasian populations (50%). The range of cancers associated with the rs6983267 variant may be larger than previously thought, and the overall contribution of this allele to the cancer burden may be large, although the individual ORs are modest. The basis of cancer susceptibility is unclear. The SNP marks a gene-poor genomic region at 8q24.21 frequently amplified in many tumor types, including colorectal and prostate cancer (2732). The SNP is located distant from any coding sequences, in the middle of a 19 kb haplotype block with a high linkage disequilibrium. The nearest genes are the putative pseudogene POU5F1P1, a transcription factor expressed in colon cancer cell lines (11), and the MYC oncogene. However, no relationship has been found between rs6983267 genotype and expression or amplification of these genes (11, 12). It is possible that the causal variant is in linkage disequilibrium with the SNP and remains unknown. The observation that allelic instability at the rs6983267 favors the risk allele in colorectal cancer tissue suggests that this locus is a target of additional somatic changes in cancer (14). If the region marked by rs6983267 is in fact associated with multisite cancer susceptibility, it is likely that the mechanism of cancer susceptibility associated this particular region is general, such as by generating chromosomal instability. Given the common occurrence of rearrangements at chromosome 8q in cancers, it is possible that rs6983267 may be marker of a fragile site, which predisposes chromosome 8 to undergo secondary chromosomal rearrangements.

No potential conflicts of interest were disclosed.

Grant support: Polish Scientific Committee grant PBZ-KBN-122/PO5/2004.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank A. Borkowski, T. Borkowski, M. Stawicka, D. Godlewski, A. Antczak, Z. Kwias, K. Krajka, W. Lauer, K. Bar, M. Sosnowski, P. Sikorska-Radek, R. Zdrojowy, B. Makiewicz, and M. Szwiec for their support in collection of DNA samples from men with prostate cancer.

1
Gudmundsson J, Sulem P, Rafnar T, et al. Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.
Nat Genet
2008
;
40
:
281
–3.
2
Eeles RA, Kote-Jarai Z, Giles GG, et al. Multiple newly identified loci associated with prostate cancer susceptibility.
Nat Genet
2008
;
40
:
316
–21.
3
Thomas G, Jacobs KB, Yeager M, et al. Multiple loci identified in a genome-wide association study of prostate cancer.
Nat Genet
2008
;
40
:
310
–5.
4
Gudmundsson J, Sulem P, Steinthorsdottir V, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.
Nat Genet
2007
;
39
:
977
–83.
5
Witte JS. Multiple prostate cancer risk variants on 8q24.
Nat Genet
2007
;
39
:
579
–80.
6
Gudmundsson J, Sulem P, Manolescu A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.
Nat Genet
2007
;
39
:
631
–7.
7
Haiman CA, Patterson N, Freedman ML, et al. Multiple regions within 8q24 independently affect risk for prostate cancer.
Nat Genet
2007
;
39
:
638
–44.
8
Yeager M, Orr N, Hayes RB, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.
Nat Genet
2007
;
39
:
645
–9.
9
Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations.
Nat Genet
2006
;
38
:
652
–8.
10
Freedman ML, Haiman CA, Patterson N, et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men.
Proc Natl Acad Sci U S A
2006
;
103
:
14068
–73.
11
Tomlinson I, Webb E, Carvajal-Carmona L, et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.
Nat Genet
2007
;
8
:
984
–8.
12
Zanke BW, Greenwood CMT, Rangrej J, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.
Nat Genet
2007
;
8
:
989
–94.
13
Haiman CA, Le Marchand L, Yamamato J, et al. A common genetic risk factor for colorectal and prostate cancer.
Nat Genet
2007
;
39
:
954
–6.
14
Tuupanen S, Niittymäki I, Nousiainen K, et al. Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution.
Cancer Res
2008
;
68
:
14
–7.
15
Stacey SN, Manolescu A, Sulem P, et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.
Nat Genet
2008
;
40
:
703
–6.
16
Hunter DJ, Kraft P, Jacobs KB, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.
Nat Genet
2007
;
39
:
870
–4.
17
Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci.
Nature
2007
;
447
:
1087
–93.
18
Cybulski C, Górski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene.
Am J Hum Genet
2004
;
75
:
1131
–5.
19
Cybulski C, Górski B, Gronwald J, et al. BRCA1 mutations and prostate cancer in Poland.
Eur J Cancer Prev
2008
;
17
:
62
–6.
20
Cybulski C, Górski B, Debniak T, et al. NBS1 is a prostate cancer susceptibility gene.
Cancer Res
2004
;
64
:
1215
–9.
21
Cybulski C, Wokołorczyk D, Huzarski T, et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer.
J Med Genet
2006
;
43
:
863
–6.
22
Cheng I, Plummer SJ, Jorgenson E, et al. 8q24 and prostate cancer: association with advanced disease and meta-analysis.
Eur J Hum Genet
2008
;
16
:
496
–505.
23
Fletcher O, Johnson N, Gibson L, et al. Association of genetic variants at 8q24 with breast cancer risk.
Cancer Epidemiol Biomarkers Prev
2008
;
7
:
702
–5.
24
Setiawan VW, Ursin G, Horn-Ross PL, et al. Germ line variation at 8q24 and endometrial cancer risk.
Cancer Epidemiol Biomarkers Prev
2007
;
16
:
2166
–8.
25
Sellick GS, Broderick P, Fielding S, Catovsky D, Houlston RS. Lack of a relationship between the common 8q24 variant rs6983267 and risk of chronic lymphocytic leukemia.
Leukemia
2008
;
22
:
438
–9.
26
Cook MB, Graubard BI, Quraishi SM, et al. Genetic variants in the 8q24 locus and risk of testicular germ cell tumors.
Hum Genet
2008
;
123
:
409
–18.
27
Ried T, Knutzen R, Steinbeck R, et al. Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors.
Genes Chromosomes Cancer
1996
;
15
:
234
–45.
28
Douglas EJ, Fiegler H, Rowan A, et al. Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas.
Cancer Res
2004
;
64
:
4817
–25.
29
Cher ML, Bova GS, Moore DH, et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping.
Cancer Res
1996
;
56
:
3091
–102.
30
Nupponen N, Visakorpi T. Molecular biology of progression of prostate cancer.
Eur Urol
1999
;
35
:
351
–4.
31
Ribeiro FR, Jeronimo C, Henrique R, et al. 8q gain is an independent predictor of poor survival in diagnostic needle biopsies from prostate cancer suspects.
Clin Cancer Res
2006
;
12
:
3961
–70.
32
van Duin M, van Marion R, Vissers K, et al. High-resolution array comparative genomic hybridization of chromosome arm 8q: evaluation of genetic progression markers for prostate cancer.
Genes Chromosomes Cancer
2005
;
44
:
438
–49.