Frequency of CHEK2 gene mutations in breast cancer patients from Republic of Bashkortostan

A number of studies demonstrated that mutations in the CHEK2 gene can increase the risk of oncologic diseases, including breast cancer and that the mutational distribution s depends on the genetic structure of populations. In our study we compared the prevalence of c.1100delC, c.444+1G>A, del5395, p.I157T, and p.R145W CHEK2 mutations in 977 breast cancer patients (Russians, Tatars, Bashkirs, Ukrainians, and individual representatives of other ethnic groups) and in women without any oncologic pathology (n = 1069) from the Republic of Bashkortostan. We found CHEK2 del5395 mutation with a frequency of 1.23% (12/977) in breast-cancer patients, whereas in the control group it frequency was 0.09% (1/1069) (OR: 13.28, CI 95%: 1.72–102.33, p = 0.003). Frequencies of c.1100delC and c.444+1G>A mutations in patients and controls were 0.4%, 0.4% (4/977) and 0.09% (1/1069), 0.2% (2/1069), respectively. The p.I157T substitution in CHEK2 gene was the most widespread variant in two studied cohorts (approximately 5%); however, differences in the frequencies between cases and controls did not reach statistical significance. Truncating mutations were mainly found in women of Slavic origin. All three mutations were found in Russians and Ukrainians. CHEK2 mutations c.1100delC and c.444+1G>A were not found in Bashkirs and Tatars; however, the CHEK2 del5395 deletion was present in Tatars.     

Low Prevalence of CHEK2 Gene Mutations in Multiethnic Cohorts of Breast Cancer Patients in Malaysia

CHEK2 is a protein kinase that is involved in cell-cycle checkpoint control after DNA damage. Germline mutations in CHEK2 gene have been associated with increase in breast cancer risk. The aim of this study is to identify the CHEK2 gene germline mutations among high-risk breast cancer patients and its contribution to the multiethnic population in Malaysia. We screened the entire coding region of CHEK2 gene on 59 high-risk breast cancer patients who tested negative for BRCA1/2 germline mutations from UKM Medical Centre (UKMMC), Hospital Kuala Lumpur (HKL) and Hospital Putrajaya (HPJ). Sequence variants identified were screened further in case-control cohorts consisting of 878 unselected invasive breast cancer patients (180 Malays, 526 Chinese and 172 Indian) and 270 healthy individuals (90 Malays, 90 Chinese and 90 Indian). By screening the entire coding region of the CHEK2 gene, two missense mutations, c.480A>G (p.I160M) and c.538C>T (p.R180C) were identified in two unrelated patients (3.4%). Further screening of these missense mutations on the case-control cohorts unveiled the variant p.I160M in 2/172 (1.1%) Indian cases and 1/90 (1.1%) Indian control, variant p.R180C in 2/526 (0.38%) Chinese cases and 0/90 Chinese control, and in 2/180 (1.1%) of Malay cases and 1/90 (1.1%) of Malay control. The results of this study suggest that CHEK2 mutations are rare among high-risk breast cancer patients and may play a minor contributing role in breast carcinogenesis among Malaysian population.     

CHEK2 1100delC, IVS2+1G>A and I157T mutations are not present in colorectal cancer cases from Turkish population

BackgroundThe cell cycle checkpoint kinase 2 (CHEK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHEK2 (1100delC, IVS2+1G>A and I157T) have been impaired serine/threonine kinase activity and associated with a range of cancer types. This hospital-based case–control study aimed to investigate whether CHEK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of colorectal cancer (CRC) in Turkish population.MethodsA total of 210 CRC cases and 446 cancer-free controls were genotyped for CHEK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods.ResultsWe did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects.ConclusionOur result demonstrate for the first time that CHEK2 1100delC, IVS2+1G>A and I157T mutations have not been agenetic susceptibility factor for CRC in the Turkish population. Overall, our data suggest that genotyping of CHEK2 mutations in clinical settings in the Turkish population should not be recommended. However, independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins.     

CHEK2 is a multiorgan cancer susceptibility gene

A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.     

Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin

CHEK2 encodes a serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways. CHEK2 directly phosphorylates and regulates the functions of p53 and BRCA1. Most women with breast and/or ovarian cancer are not carriers of mutant BRCA1 or BRCA2. Multiple studies have shown that a CHEK2*1100delC confers about a two-fold increased risk of breast cancer in unselected females and a tenfold increase in males. Moreover, studies have shown that first-degree relatives of bilateral breast cancer cases who carried the CHEK2*1100delC allele had an eight-fold increased risk of breast cancer. It has been suggested that CHEK2 functions as a low-penetrance susceptibility gene for cancers and multiplies the risks associated with other gene(s) to increase cancer risk. The main goal of this study was to evaluate and to compare the role of truncating mutations, splice junction mutations and rare missense substitutions in breast cancer susceptibility gene CHEK2. Present study was performed on 140 individuals including 70 breast cancer patients both with and without family history and 70 normal individuals. Written consent was obtained and 3 ml intravenous blood was drawn from all the subjects. DNA was extracted from all the samples through inorganic method published already. Primers were synthesized for all the 14 exons of CHEK2 gene. Coding and adjacent intronic sequences of CHEK2 gene were amplified and sequenced. Two genetic variants (p.H371Y, p.D438Y) were found in exon 10 and exon 11 of gene CHEK2 which were not found in any of the 70 control individuals from same geographical area and ethnic group. The genetic variant c.1312G>T (p.D438Y) identified in a patient with a family history of breast cancer. To our knowledge, this is first mutation scanning study of gene CHEK2 from Balochistan population.     

CHEK2 gene alterations in the forkhead-associated domain, 1100delC and del5395 do not modify the risk of sporadic pancreatic cancer

Checkpoint kinase 2 gene (CHEK2) alterations increase risk of several cancer types. We analyzed selected CHEK2 alterations in 270 Czech pancreatic cancer patients and in 683 healthy controls. The pancreatic cancer risk was higher in individuals who inherited rare alterations in CHEK2 region involving forkhead-associated domain other than I157T (OR = 5.14; 95% CI = 0.94–28.23) but the observed association was non-significant (p = 0.057). The most frequent I157T mutation did not alter the pancreatic cancer risk and neither the followed deletion of 5395 bp nor c.1100delC were found in any of pancreatic cases. We conclude that the I157T, other alterations in its proximity, del5395 and c.1100delC in CHEK2 do not predispose to pancreatic cancer risk in the Czech population.     

Case report of a woman with monoclonal gammapathy and papillary thyroid carcinoma, diagnosed because of detection of CHEK2 (I157T) mutation in genetic examinations

The CHEK2 gene encodes the CHK2 protein, which is kinase involved in DNA repair processes. By activating a lot of cell substrates, it can regulate the cell cycle, demonstrates suppressive effects, and participates in the senescence and apoptosis processes. Mutations in the CHEK2 gene are associated with increased risk of numerous cancers. The case described herein is that of a woman with a missense mutation that results in the substitution of isoleucine for threonine at position 157. This variant of the mutation doubles the risk of papillary thyroid carcinoma two times and causes up to 9% of these cancer. It is also associated with a two-fold increased risk of cancers of the kidney (10%), colon (10%), and ovary (10% - G1), a 1.6-fold increased risk of prostate cancer (8% of all of them and 12% of familiar ones), and a 1.5-fold increased risk of breast cancer (7%). The screening procedures were initiated in a carrier who revealed papillary thyroid carcinoma. Genetic screening of the family diagnosed her daughter as the carrier of this mutation. Until now no active cancer disease has been recognized in the daughter. On the example of the presented case we discuss indications for screening in cases of positive family history. The group especially predisposed seem to be patients with at least two coexisting carcinomas. Having diagnosed the mutation, it is necessary to do genetic screening of family members. Continuous oncological observation of the carriers of CHEK 2 mutation is essential.     

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants reported elsewhere, R145W and I157T with breast cancer, we screened 737 BRCA1/2-negative familial breast cancer cases from 605 families, 459 BRCA1/2-positive cases from 335 families, and 723 controls from the United Kingdom, the Netherlands, and North America. All three variants were rare in all groups, and none occurred at significantly elevated frequency in familial breast cancer cases compared with controls. These results indicate that 1100delC may be the only CHEK2 allele that makes an appreciable contribution to breast cancer susceptibility.     

A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer

CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63; P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0002), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women.     

Meta-analysis of the NAD(P)H: quinine oxidoreductase 1 gene 609 C>T polymorphism with esophageal cancer risk

Association between the NAD(P)H: quinine oxidoreductase 1 (NQO1) gene 609 C>T polymorphism and esophageal cancer (EC) has been widely evaluated; however, the results are often irreproducible. We thus aimed to comprehensively evaluate this association through a meta-analysis. Data were extracted from 10 study populations involving 1390 EC patients and 1812 controls, and were analyzed using STATA software. Random-effects model was applied irrespective of between-study heterogeneity, which was assessed by the inconsistency index (I(2)) statistic. Publication bias was weighted by the funnel plot and Egger's test. Genotype distributions of the NQO1 gene 609 C>T polymorphism met Hardy-Weinberg equilibrium in controls for all studies. Allelic comparison indicated that NQO1 609 T allele conferred an increased risk (odds ratio [OR]=1.23; 95% confidence interval [CI]: 1.02-1.49; p=0.035), accompanying significant heterogeneity (I(2)=63.4%, p=0.003) and no publication bias (p(Egger)=0.391). This association was potentially enhanced in homozygous comparison (OR=1.58; 95% CI: 1.03-2.41; p=0.035; I(2)= 55.4%, p(heterogeneity)=0.017 and p(Egger)=0.461). Under dominant and recessive models, similar associations were obtained with an increased, although marginally significant risk. Subgroup analysis by ethnicity supported the risk profiles of the NQO1 gene 609 T allele and 609 TT genotype with EC in Eastern Asians, not in Europeans. Meta-regression analysis indicated that association between the NQO1 gene 609 C>T polymorphism and EC risk was significantly decreased with aging in case-patients (R(2)=-0.57; p=0.042). We expand previous studies by showing that the NQO1 gene 609 C>T polymorphism might contribute to EC occurrence, especially in Eastern Asians.     

Association between the p73 exon 2 G4C14-to-A4T14 polymorphism and cancer risk: a meta-analysis

The TP53 homolog p73 is structurally and functionally similar to TP53 and plays an important role in modulating cell-cycle control, apoptosis, and cell growth. G4C14-to-A4T14 is the most commonly studied polymorphism of this gene for its association with risk of cancers, but the results are confusing rather than conclusive. We performed a meta-analysis using 21 eligible studies with a total of 7581 patients and 10,413 controls to summarize the data for an association between the p73 G4C14-to-A4T14 polymorphism and cancer risk. Compared with the common GC/GC genotype, the AT carriers (AT/GC, AT/AT) had a 1.18-fold elevated risk of cancer (95% confidence interval [CI]=1.11-1.25, p<0.00001) in a dominant genetic model as estimated in a fixed effect model. The effect of the G4C14-to-A4T14 polymorphism was further evaluated through stratification analysis. In four lung cancer studies, the variant genotypes had a significantly increased risk of lung cancer (odds ratio [OR]=1.16, 95% CI=1.04-1.28, p=0.005). Similar phenomena were also found in two squamous cell carcinoma of the head and neck studies (OR=1.32, 95% CI=1.12-1.56, p=0.0010), two oral cancer studies (OR=1.57, 95% CI=1.26-1.95, p<0.0001), and three colorectal cancer studies (OR=1.23, 95% CI=1.01-1.50, p=0.04). Increased risk of cancer associated with G4C14-to-A4T14 variant genotypes was pronounced in Caucasians (OR=1.21, 95% CI=1.11-1.31, p<0.00001), the Japanese population (OR=1.24, 95% CI=1.01-1.52, p=0.04), and the Korean population (OR=1.27, 95% CI=1.07-1.52, p=0.007). Our meta-analysis suggests that the p73 G4C14-to-A4T14 polymorphism genotypes (GC/AT+AT/AT) may be associated with an increased risk of cancer in most cancer types and ethnicities.     

MDR1 single nucleotide polymorphism C3435T in Turkish patients with non-small-cell lung cancer

We assessed whether single nucleotide polymorphisms (SNPs) in MDR1 gene C3435T predicted the outcome of platinum-based chemotherapies and survival in our non small cell lung cancer (NSCLC) patients. A total of 79 non-small cell lung cancer patients were enrolled to study. We determined the MDR1 C3435T single nucleotide gene polymorphisms. Median age was 60years: 91.7% male, 8.9% female. We found that CC, CT, TT genotype and T, C allele frequencies in lung cancer patients as 24.1%, 62%, 13.9% and 44.3%, 55.7%, respectively. Patients with CT genotype had a higher response rate (11.4%) than the other genotypes. However, this difference is not statistically significant (p=0.743). Cox regression analysis for overall survival showed that ECOG PS status 0 (HR PS 1 vs. 0, 5.68 p=0.002; HR of PS 2 vs. 0 is 21.579, p=0.001; HR of PS 3 vs. 0 is 35.35, p=0.001), stage ≤II (HR of stage III vs. I+II is 17.77; p=0.016, HR of stage IV vs. I+II is 26.97, p=0.006), and albumin level ≥3g/dl (HR of albumin <3g/dl vs. ≥3g/dl is 2.46, p=0.044) were the most important prognostic factors (also, time to progression was related to these factors). There was no significant association between the genotypes and clinicopathologic parameters; however, good performance status, early stage and ≥3g/dl albumin level were found to be the most important prognostic factors for overall survival and progression-free survival.     

Identification of a novel germline BRCA2 variant in a Chinese breast cancer family

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer‐related deaths in women worldwide. In this study, a large Chinese pedigree with breast cancer including a proband and two female patients was recruited and a familial history of breast cancer was collected by questionnaire. Clinicopathological assessments and neoadjuvant therapy‐related information were obtained for the proband. Blood samples were taken, and gDNA was extracted. The BRCA1/2 and PALB2 genes were screened using next‐generation sequencing by a targeted gene panel. We have successfully identified a novel, germline heterozygous, missense mutation of the gene BRCA2: c.7007G>T, p.R2336L, which is likely to be pathogenic in the proband and her elder sister who both had breast cancer. Furthermore, the risk factors for developing breast cancer in this family are discussed. Thus, genetic counselling and long‐term follow‐up should be provided for this family of breast cancer patients as well as carriers carrying a germline variant of BRCA2: c.7007G>T (p.R2336L).     

Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair

Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma. The association of MC1R gene variants with nonmelanoma skin cancer is largely unknown. A total of 838 subjects were included in the present study: 453 patients with nonmelanoma skin cancer and 385 subjects with no skin cancer. The coding sequence of the human MC1R gene was tested using single-stranded conformation polymorphism analysis followed by sequencing of unknown variants. Risk of skin cancer dependent on the various MC1R gene variants was estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair skin and red hair. A total of 27 MC1R gene variants were found. The number of carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (24.8%), and 7 (0.9%), respectively. A strong association between MC1R gene variants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P < .0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds ratio 3.77; 95% confidence interval [CI] 2.11-6.78), nodular basal cell carcinoma (odds ratio 2.26; 95% CI 1.45-3.52), and superficial multifocal basal cell carcinoma (odds ratio 3.43; 95% CI 1.92-6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. The highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk was only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp variant alleles. When subjects were stratified by skin type and hair color, analysis showed that these factors did not materially change the relative risks. These findings indicate that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer.     

The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype

Because of genetic heterogeneity, the identification of breast cancer-susceptibility genes has proven to be exceedingly difficult. Here, we define a new subset of families with breast cancer characterized by the presence of colorectal cancer cases. The 1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380 families with non-HBCC (P<.001), thus providing genetic evidence for the HBCC phenotype. The CHEK2 1100delC mutation was, however, not the major predisposing factor for the HBCC phenotype but appeared to act in synergy with another, as-yet-unknown susceptibility gene(s). The unequivocal definition of the HBCC phenotype opens new avenues to search for this putative HBCC-susceptibility gene.     

Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk

To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.     

Association of Toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population

Prostate cancer (PCa) is the most common cancer among men. It has been suggested that toll like receptors (TLRs) may contribute to PCa pathogenesis by stimulating prostate epithelial cell proliferation in response to infectious stimuli. We performed case control study to analyze the genetic variants of TLR2, 3 and 9 gene polymorphisms with PCa risk in a North Indian population. For this study we genotyped age matched, unrelated 195 PCa patients and 250 healthy controls of similar ethnicity in a case-control study. They were genotyped for TLR2 (-196 to -174 Del), TLR3 (c.1377C/T) [rs3775290] and TLR9 (G2848A) [rs352140] gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism method. Variant allele Del (D) carriers i.e. (ID + DD) of TLR2 (-196 to -174 Del) SNP, demonstrated 1.57 fold increased risk (p = 0.040; OR = 1.57, 95% CI = 1.02-2.24) as compared to Ins (I) allele, suggesting a dominant effect model involved in the risk of this polymorphism in PCa. However, variants of TLR3 and 9 gene polymorphisms were not associated with PCa risk. Our results suggested the low penetrance variant of TLR2 (-196 to -174 Del) to be at increased PCa risk in North Indian population. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for PCa etiology.     

CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies

Previous studies of families with multiple cases of breast cancer have indicated that a frameshift alteration in the CHEK2 gene, 1100delC, is associated with an elevated frequency of breast cancer in such families, but the risk associated with the variant in other situations is uncertain. To evaluate the breast cancer risk associated with this variant, 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in five countries were genotyped. CHEK2*1100delC was found in 201 cases (1.9%) and 64 controls (0.7%) (estimated odds ratio 2.34; 95% CI 1.72–3.20; P=.0000001). There was some evidence of a higher prevalence of CHEK2*1100delC among cases with a first-degree relative affected with breast cancer (odds ratio 1.44; 95% CI 0.93–2.23; P=.10) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis (P=.002). These results confirm that CHEK2*1100delC confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results are consistent with the hypothesis that CHEK2*1100delC multiplies the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.