Variants in the CHEK2 have been found to be associated with prostate cancer risk in the United States and Finland. We sequenced CHEK2 gene in 140 Polish patients with prostate cancer and then genotyped the three detected variants in a larger series of prostate cancer cases and controls. CHEK2 truncating mutations (IVS2 ؉ 1G>A or 1100delC) were identified in 9 of 1921 controls (0.5%) and in 11 of 690 (1.6%) unselected patients with prostate cancer [odds ratio (OR) ‫؍‬ 3.4; P ‫؍‬ 0.004]. These mutations were found in 4 of 98 familial prostate cases (OR ‫؍‬ 9.0; P ‫؍‬ 0.0002). The missense variant I157T was also more frequent in men with prostate cancer (7.8%) than in controls (4.8%), but the relative risk was more modest (OR ‫؍‬ 1.7; P ‫؍‬ 0.03). I157T was identified in 16% of men with familial prostate cancer (OR ‫؍‬ 3.8; P ‫؍‬ 0.00002). Loss of the wild-type CHEK2 allele was not observed in any of prostate cancers from five men who carried CHEK2-truncating mutations. Our results provide evidence that the two truncating mutations of CHEK2 confer a moderate risk of prostate cancer in Polish men and that the missense change appears to confer a modest risk.

Background:To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients.Methods:Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5).Results:The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ⩽60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases.Conclusion:A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.

Background: Germline mutations in the Chek2 kinase gene (CHEK2) have been associated with a range of cancer types. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin. The geographical and ethnic extent of this founder allele has not yet been determined. Participants and methods: We assayed for the presence of this deletion, and of three other CHEK2 founder mutations, in 1864 patients with prostate cancer and 5496 controls from Poland. Results: The deletion was detected in 24 of 5496 (0.4%) controls from the general population, and is the most common CHEK2 truncating founder allele in Polish patients. The deletion was identified in 15 of 1864 (0.8%) men with unselected prostate cancer (OR 1.9; 95% CI 0.97 to 3.5; p = 0.09) and in 4 of 249 men with familial prostate cancer (OR 3.7; 95% CI 1.3 to 10.8; p = 0.03). These ORs were similar to those associated with the other truncating mutations (IVS2+1GRA, 1100delC). Conclusion: A large deletion of exons 9 and 10 of CHEK2 confers an increased risk of prostate cancer in Polish men. The del5395 founder deletion might be present in other Slavic populations, including Ukraine, Belarus, Russia, Baltic and Balkan countries. It will be of interest to see to what extent this deletion is responsible for the burden of prostate cancer in other populations.

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]

To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P ‫؍‬ 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P ‫؍‬ 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.

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Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.

The G84E mutation predisposes to prostate cancer in Poland, but accounts for only a small proportion of cases. We expect that the G84E founder mutation might be present in other Slavic populations.