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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 (4 ng ml−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+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Backgroud Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers. Methods In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFα) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls). Results Of the six genes only one polymorphism in TNFα(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFα -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFα -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs). Conclusion The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.

The APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation (c.783delG, p.Val262Phefs) in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls (OR = 0.95, 95% CI 0.56-1.59, p = 0.94). The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases (OR = 0.80, 95% CI 0.35-1.83, p = 0.74). Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene.

Several breast cancer susceptibility genes have been discovered, but more are likely to exist. To identify additional breast cancer susceptibility genes, we used the founder population of Poland and performed whole-exome sequencing on 510 women with familial breast cancer and 308 control subjects. We identified a rare mutation in ATRIP (GenBank: NM&#95;130384.3: c.1152&#95;1155del [p.Gly385Ter]) in two women with breast cancer. At the validation phase, we found this variant in 42/16,085 unselected Polish breast cancer-affected individuals and in 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). By analyzing the sequence data of the UK Biobank study participants (450,000 individuals), we identified ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). Immunohistochemistry and functional studies showed the ATRIP c.1152&#95;1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. We showed that tumors of women with breast cancer who have a germline ATRIP mutation have loss of heterozygosity at the site of ATRIP mutation and genomic homologous recombination deficiency. ATRIP is a critical partner of ATR that binds to RPA coating single-stranded DNA at sites of stalled DNA replication forks. Proper activation of ATR-ATRIP elicits a DNA damage checkpoint crucial in regulating cellular responses to DNA replication stress. Based on our observations, we conclude ATRIP is a breast cancer susceptibility gene candidate linking DNA replication stress to breast cancer., Competing Interests: Declaration of interests M.R.A. has equity ownership in Genewsie Inc., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: The BRCA2 p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the ALDH2 gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the BRCA2 p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein., Materials and Methods: We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic BRCA2 mutations., Results: BRCA2 p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the ALDH2 rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; P = .003). The BRCA2 p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the ALDH2 rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; P = .81). In the carriers of high-risk BRCA2 mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk., Conclusion: Our results suggest that BRCA2 p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the ALDH2 rs10744777 variant in the Polish population., Competing Interests: Mohammad R. AkbariStock and Other Ownership Interests: GenewisePatents, Royalties, Other Intellectual Property: Breast Cancer Biomarkers (RECQL) and Methods of Diagnosis, Patent No. US 10,131,957 B2 (Inst), Breast Cancer Biomarkers (RECQL) and Methods of Treatment, Patent No. US 9,926,607 B2 (Inst)No other potential conflicts of interest were reported.

The goal of this study was to estimate the risk of thyroid cancer following breast cancer and to identify therapeutic and genetic risk factors for the development of thyroid cancer after breast cancer. We followed 10,832 breast cancer patients for a mean of 14 years for new cases of thyroid cancer. All women were genotyped for three Polish founder mutations in BRCA1 (C61G, 4153delA, 5382insC) and four mutations in CHEK2 (1100delC, IVS2 + 1G/A, del5395, I157T). Information was collected on chemotherapy, radiotherapy, hormonal therapies, and oophorectomy. Of the 10,832 women, 53 (0.49%) developed a second primary thyroid cancer. Based on Polish population statistics, the expected number was 12.4 (SIR = 4.3). The ten-year risk of developing thyroid cancer was higher in women who carried a CHEK2 mutation (1.5%) than in women who carried no mutation (0.9%). The age-adjusted hazard ratio for developing thyroid cancer was 1.89 (0.46-7.79; p = 0.38) for those with a CHEK2 protein-truncating mutation and 2.75 (1.29-5.85; p = 0.009) for those with a CHEK2 missense mutation.

The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p -values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

Background: Breast cancer in men accounts for fewer than 1 % of all breast cancer cases diagnosed in men and women. Genes which predispose to male breast cancer include BRCA1 and BRCA2. The role of other genes is less clear. In Poland, 20 founder mutations in BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL are responsible for the majority of hereditary breast cancer cases in women, but the utility this genes panel has not been tested in men., Methods: We estimated the prevalence of 20 alleles in six genes (BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL) in 165 Polish male breast cancer patients. We compared the frequency of selected variants in male breast cancer cases and controls., Results: One of the 20 mutations was seen in 22 of 165 cases (13.3%). Only one BRCA1 mutation and two BRCA2 mutations were found. We observed statistically significant associations for PALB2 and CHEK2 truncating mutations. A PALB2 mutation was detected in four cases (OR = 11.66; p < 0.001). A CHEK2 truncating mutation was detected in five cases (OR = 2.93;p = 0.02)., Conclusion: In conclusion, we recommend that a molecular test for BRCA1, BRCA2, PALB2 and CHEK2 recurrent mutations should be offered to male breast cancer patients in Poland., (© 2021. The Author(s).)

Background: The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers., Methods: We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509&#95;510delGA and c.172&#95;175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers., Results: A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006)., Conclusion: In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The role of PALB2 in carcinogenesis remains to be clarified. Our main goal was to determine the prevalence of PALB2 (509&#95;510delGA and 172&#95;175delTTGT) mutations in bladder and kidney cancer patients from Polish population., Materials and Methods: 1413 patients with bladder and 810 cases with kidney cancer and 4702 controls were genotyped for two PALB2 variants: 509&#95;510delGA and 172&#95;175delTTGT., Results: Two mutations of PALB2 gene were detected in 5 of 1413 (0.35%) unselected bladder cases and in 10 of 4702 controls (odds ratio [OR], 1.7; 95% CI 0.56-4.88; p = 0.52). Among 810 unselected kidney cancer cases two PALB2 mutations were reported in two patients (0,24%) (odds ratio [OR], (OR = 1.2; 95% CI 0.25-5.13; p = 0.84). In cases with mutations in PALB2 gene cancer family history was negative., Conclusion: We found no difference in the prevalence of recurrent PALB2 mutations between cases and healthy controls. The mutations in PALB2 gene seem not to play a major role in bladder and kidney cancer development in Polish patients.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy., (© 2020 Union for International Cancer Control.)

To optimize genetic testing, it is necessary to establish the spectrum of breast cancer-predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non-BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2-positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non-BRCA-positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide., (© 2019 UICC.)

Background: XRCC2 participates in homologous recombination and in DNA repair. XRCC2 has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer susceptibility gene panels., Methods: We sequenced XRCC2 in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the XRCC2 founder mutation., Results: We identified a recurrent truncating mutation of XRCC2 (c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48-1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27-2.65). Breast cancers in XRCC2 mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type XRCC2 allele was observed only in one of the eight breast cancers from patients who carried the XRCC2 mutation. No cancer type was more common in first- or second-degree relatives of XRCC2 mutation carriers than in relatives of the non-carriers., Conclusion: XRCC2 c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider XRCC2 as a breast cancer-predisposing gene.

Background: NBN 657del5 founder mutation predisposes to breast and prostate cancer. Recently, it has been reported that the pathogenicity of this mutation with regard to prostate cancer risk is modified by a missense variant of the same gene (E185Q)., Methods: To evaluate the interaction of the 657del5 and E185Q founder alleles of NBN on breast cancer risk in Poland, 4964 women with breast cancer and 6152 controls were genotyped for these two recurrent variants of NBN (657del5 truncating variant and E185Q missense variant)., Results: The NBN 657del5 mutation was detected in 57 of 4964 unselected cases and in 35 of 6152 controls (OR = 2.0, p = 0.001). The E185Q GG genotype was detected in 2167 of 4964 unselected cases and in 2617 of 6152 controls (OR = 1.04, p = 0.3). In carriers of the 657del5 deletion, the elevated cancer risk was restricted to women with the GG genotype of the E185Q variant (OR = 3.6, 95% CI 1.9-6.6; p < 0.0001). Among women with other E185Q genotypes, the OR associated with 657del5 was 1.0 (95% CI 0.5-1.8; p = 0.9). The interaction between the two alleles was statistically significant (homogeneity p = 0.003)., Conclusion: In Poland, the pathogenicity of the NBN 657del5 mutation is restricted to women with a homozygous GG genotype of missense variant of the same gene (E185Q). This is the first clear example whereby a moderate penetrance breast cancer gene is impacted by a genetic modifier.

Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6-1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region., (© The Author 2015. Published by Oxford University Press.)

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.)

Background: Mutations in PALB2 predispose to breast cancer, but the effect on prognosis of carrying a PALB2 mutation has not been ascertained. We aimed to estimate the odds ratio for breast cancer in women with an inherited mutation in PALB2 and 10-year survival after breast cancer in patients who carry a PALB2 mutation., Methods: Between 1996 and 2012, patients with invasive breast cancer were recruited prospectively from 18 hospitals in Poland and genotyped for two deleterious mutations in PALB2 (509&#95;510delGA and 172&#95;175delTTGT). A control group of 4702 women without cancer was recruited for comparison. The primary endpoint was death from any cause, as determined by medical records from the Polish Ministry of the Interior and Administration. In patients with breast cancer, 10-year survival of carriers of a PALB2 mutation was calculated and compared with that of non-carriers., Findings: 17 900 women with breast cancer were invited to participate, of whom 12 529 were genotyped successfully. A PALB2 mutation was present in 116 (0·93%, 95% CI 0·76-1·09) of 12 529 patients and in ten (0·21%, 0·08-0·34) of 4702 controls (odds ratio 4·39, 95% CI 2·30-8·37; p<0·0001). 10-year survival for women with breast cancer and a PALB2 mutation was 48·0% (95% CI 36·5-63·2), compared with 74·7% (73·5-75·8) for patients with breast cancer without a mutation (adjusted hazard ratio for death 2·27, 95% CI 1·64-3·15; p<0·0001)., Interpretation: Women with a PALB2 mutation face an increased risk of breast cancer and might be at a higher risk of death from breast cancer compared with non-carriers. Increased surveillance should be offered to unaffected women who carry a PALB2 mutation., Funding: Polish National Science Centre., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667&#95;1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

A nonsense mutation, p.Q548X, in the BLM gene has recently been associated with an increased risk for breast cancer. In the present work, we investigated the prevalence of this Slavic founder mutation in 2,561 ovarian cancer cases from Russia, Belarus, Poland, Lithuania or Germany and compared its frequency with 6,205 ethnically matched healthy female controls. The p.Q548X allele was present in nine ovarian cancer patients of Slavic ancestry (0.5 %; including one case with concurrent BRCA1 mutation). The mutation was not significantly more frequent in cases than in controls (Mantel-Haenszel OR 1.14, 95 % CI 0.49; 2.67). Ovarian tumours in p.Q548X carriers were mainly of the serous subtype, and there was little evidence for an early age at diagnosis or pronounced family history of cancer. These findings indicate that the BLM p.Q548X mutation is not a strong risk factor for ovarian cancer.

A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA-XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR=2.60; p<0.001) and with the AA genotype (OR=531; p<0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer., (Copyright © 2014. Published by Elsevier B.V.)

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test., (© 2013 UICC.)