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Wokolorczyk D.,Pomeranian Medical University | Gliniewicz B.,Pomeranian Medical University | Stojewski M.,Pomeranian Medical University | Sikorski A.,Pomeranian Medical University | And 8 more authors.
European Journal of Cancer Prevention | Year: 2010

Several recent association studies implicate three neighbouring regions of chromosome 8q24 as the site of prostate cancer susceptibility loci. One region contains both a microsatellite marker DG8S737 and a single nucleotide polymorphism rs1447295. Both have been consistently associated with prostate cancer risk in several populations. However, studies to date have not inquired whether the susceptibility associated with this particular region of 8q24 extends to other cancer sites. We genotyped 3822 cases of cancer of various sites and 1807 controls for rs1447295 polymorphism. A positive association was seen for prostate cancer, but not for any of the other sites studied [odds ratios (ORs) ranging from 0.8 to 1.1]. Prostate cancer cases and controls were genotyped for both rs1447285 and DG8S737. Significant ORs were observed for the A allele of rs1447285 (OR = 1.4; P = 0.01) and the -8 allele of DG8S737 (OR = 1.6; P = 0.006). The association was particularly strong for men with familial prostate cancer (OR = 2.0, P = 0.004 for the A allele; OR = 3.5, P<0.0001 for the -8 allele). The OR associated with the A allele of rs1447295 was slightly higher for aggressive tumours (Gleason score 8 or more) (OR = 1.5), than for tumours with Gleason score 7 and below (OR = 1.3). In conclusion, the relationship between the rs1447295 and DG8S737 polymorphic variants on chromosome 8q24 and prostate cancer risk is seen in the Polish population to a similar degree as it has been observed elsewhere. Although the carcinogenic mechanism associated with this particular locus of 8q24 is unclear it appears to be specific to prostate cancer. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Siolek M.,Holycross Cancer Center | Cybulski C.,Pomeranian Medical University | Gasior-Perczak D.,Holycross Cancer Center | Kowalik A.,Holycross Cancer Center | And 13 more authors.
International Journal of Cancer | Year: 2015

Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 + 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid. © 2015 UICC. Source


Kluzniak W.,Pomeranian Medical University | Wokolorczyk D.,Pomeranian Medical University | Kashyap A.,Pomeranian Medical University | Jakubowska A.,Pomeranian Medical University | And 33 more authors.
Prostate | Year: 2013

BACKGROUND The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20-fold). The geographical and ethnic extent of this recurrent allele has not yet been determined. METHODS We assayed for the presence of the G84E mutation in 3,515 prostate cancer patients and 2,604 controls from Poland and estimated the odds ratio for prostate cancer associated with the allele. RESULTS The G84E mutation was detected in 3 of 2,604 (0.1%) individuals from the general population in Poland and in 20 of 3,515 (0.6%) men with prostate cancer (Odds ratio [OR] = 5.0; 95% CI: 1.5-16.7; P = 0.008). The allele was present in 4 of 416 (1.0%) men with familial prostate cancer (OR = 8.4, 95% CI: 1.9-37.7; P = 0.005). CONCLUSIONS 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. Copyright © 2013 Wiley Periodicals, Inc. Source


Cybulski C.,Pomeranian Medical University | Wokolorczyk D.,Pomeranian Medical University | Kluzniak W.,Pomeranian Medical University | Kashyap A.,Pomeranian Medical University | And 28 more authors.
British Journal of Cancer | Year: 2013

Background: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. Methods: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4ngml -1) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G4A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine lowrisk single-nucleotide polymorphisms (SNPs). Results: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). Conclusion: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal. © 2013 Cancer Research UK. All rights reserved. Source


Cybulski C.,Pomeranian Medical University | Wokolorczyk D.,Pomeranian Medical University | Kluzniak W.,Pomeranian Medical University | Jakubowska A.,Pomeranian Medical University | And 54 more authors.
British Journal of Cancer | Year: 2013

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. © 2013 Cancer Research UK. All rights reserved. Source

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