A <Emphasis Type="Italic">CYP19</Emphasis> (aromatase) polymorphism is associated with increased premenopausal breast cancer risk

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20–2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74–8.70] and OR = 2.52 [1.26–5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82–1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.     

Genetic polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> (codon 399) and susceptibility to breast cancer in Iranian women,a case–control study

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. In the present study, we specifically investigated whether common genetic variant in XRCC1 (exon 10, codon Arg399Gln) was associated with an altered risk of breast cancer. The eligible cases were patients at chemotherapy unit of Nemazi hospital, Shiraz Iran, from October 1999 to August 2000 and from July 2004 to July 2005. The present study included 186 females with breast cancer. Age frequency-matched controls were randomly selected from the healthy females blood donor, according to the age distribution of the cases. A total of 187 healthy females included in the study. Using PCR-based method, the XRCC1 Arg399Gln polymorphism was determined. In control group the 399Gln allele frequency was 32.6%. The genotypic frequencies of the control subjects did not show significant deviation from Hardy-Weinberg equilibrium (χ² = 1.683, df = 1, P > 0.05). A statistically significant association was observed in comparison between Gln/Gln and Arg/Arg genotype (OR = 2.01, 95% CI:1.02–3.94, P = 0.041). There was no linear trend for presence of 0, 1, and 2 of the 399Gln allele and risk of breast cancer (χ² = 1.212, P = 0.271). In the recessive effect of the Gln allele (comparison between Gln/Gln vs. Arg/Arg+Arg/Gln), Gln/Gln genotype significantly increased the risk of breast cancer (OR = 2.31, 95% CI:1.21–4.35, P = 0.010). In the dominant effect of the Gln allele (comparison between Gln/Gln+Arg/Gln vs. Arg/Arg), Gln/Gln+Arg/Gln genotypes was not associated with the risk of breast cancer (OR = 0.95, 95% CI:0.63–1.42, P = 0.799). It is concluded that 399Gln allele may act as a recessive allele and increase the breast cancer risk. This study was supported by Shiraz University.     

A role for the p53 pathway in the pathology of meningiomas with <Emphasis Type="Italic">NF2</Emphasis> loss

The neurofibromatosis 2 locus (NF2) is inactivated through mutation and loss of heterozygosity (LOH) in 40–65% of all sporadic meningiomas, while the role of the p53 tumor suppression pathway in meningioma initiation and progression is still unclear. This study aims to determine if a p53 codon 72 arginine-to-proline polymorphism, found to be correlated with cancer development and cancer patient survival in other tumors, is associated with sporadic meningioma initiation or progression. We investigated Pro72 incidence in a cohort of 92 sporadic meningiomas and analyzed its association with histological grade (WHO classification) and with NF2 LOH (determined using polymorphic microsatellite markers on 22q). The Pro72 allele was not found to be selected for in the cohort. However, in the subgroup of meningiomas with NF2 LOH and carrying Pro72, 50.0% had high grade tumors (WHO grades II and III) compared to only 14.3% of those without NF2 LOH (OR = 6.0, CI = 1.56–23.11, P = 0.012). The significant association occurred only when considering subgroups of meningiomas with or without NF2 LOH, suggesting that not including NF2 status when analyzing study cohorts may explain the variability seen in the literature where all meningiomas were grouped together. Our data suggests a role for the p53 pathway in the progression of meningiomas in which NF2 is inactivated, and highlights the importance of accounting for NF2 LOH in future studies of meningiomas and the p53 pathway.     

Allelic loss at the BRCA1, BRCA2 and TP53 loci in human sporadic breast carcinoma

Abnormalities in several genes are known to confer susceptibility to breast cancer. In the present study, we investigated the incidence of allelic imbalance at the BRCA1, BRCA2 and TP53 loci, in 82 sporadic breast carcinomas using a bank of highly polymorphic microsatellite markers located at the BRCA1, BRCA2 and TP53 regions. Genetic alterations were observed in 58/82 (71%) cases in at least one microsatellite marker, at one of the three regions. Twenty-seven out of 82 (33%) cases exhibited loss of heterozygosity (LOH) at BRCA1 locus while in 20/82 (34%) cases LOH was observed for the BRCA2 region. Allelic deletions were detected in 28/82 (34%) cases for the TP53 locus. Our results suggest that allelic deletion at the above genetic loci play an important role to the development of sporadic breast tumours.     

Fok1 polymorphism of vitamin D receptor gene contributes to breast cancer susceptibility: a meta-analysis

Several polymorphisms in the vitamin D receptor (VDR) gene have been reported to influence breast cancer risk. However, the published findings have been conflicting. We conducted a meta-analysis of 21 case–control studies with Fok1 (eight studies with 5,284 cases and 7,500 controls), Bsm1 (14 studies with 5,498 cases and 7,943 controls), Apa1 (four studies with 1,138 cases and 7,943 controls), Taq1 (10 studies with 4,459 cases and 5,485 controls) polymorphisms. The results showed Fok1 polymorphism was associated with an overall significantly increased risk of breast cancer (ff vs. FF: OR = 1.15, 95% CI = 1.03–1.28; the recessive model ff vs. Ff + FF: OR = 1.14, 95% CI = 1.03–1.26). In subgroup analysis, a significant association was evident between Fok1 polymorphism and breast cancer in European population (ff vs. FF: OR = 1.16, 95% CI = 1.04–1.30; the recessive model ff vs. Ff + FF: OR = 1.15, 95% CI = 1.04–1.28). There was no between-study heterogeneity in any of these analyses. No significant associations were observed between the Bsm1, Apa1 and Taq1 variants and breast cancer risk. So, the current meta-analysis shows that Fok1 may be a susceptibility biomarker for breast cancer especially in European population.     

Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, hyperhomocysteinaemia and increased risk for atherosclerosis in homozygotes. We examined the frequency of this mutation and its association with disease pattern in 491 Jewish women with either sporadic (n=355; 72%) or hereditary (n=136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2 mutation carriers, genotyped for the three predominant Jewish founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes were equally distributed among women with sporadic breast and/or ovarian cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205; 21.0%) (P=non-significant). 677T homozygotes were equally distributed among women diagnosed with breast cancer prior to (22/122; 18.0%) and after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes in manifesting cancer (32/136; 23.5%) and asymptomatic individuals (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among women with bilateral breast cancer and those with both breast and ovarian carcinoma than among those with unilateral breast cancer (64/365; 17.5%). Differences in morbidity (one versus multiple breast/ovarian tumours) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations. Confirmation of these data, namely, that the 677T allele is significantly more common in cases of bilateral breast cancer or combined breast and ovarian cancer would have important clinical implications.     

Polymorphisms in DNA repair gene <Emphasis Type="Italic">XRCC1</Emphasis> and increased genetic susceptibility to breast cancer

X-ray repair cross-complementing 1 (XRCC1) gene encodes for a scaffolding protein, which plays an important role in base excision DNA repair by bringing together DNA polymerase beta, DNA ligase III and poly(ADP-Ribose) polymerase (PARP) at the site of DNA damage. Three polymorphisms of the XRCC1 gene at codons 194, 280 and 399 leading to a mino acid changes at evolutionary conserved regions are found to alter the efficiency of the resulting protein and may therefore constitute potential breast cancer risk. In the present study we sought to determine whether these genetic variants of the XRCC1 gene was associated with any increased risk of breast cancer among the South Indian women in a hospital based case control study using PCR-RFLP and DNA sequencing techniques. Our data showed a positive association between the polymorphisms of codons 194 (OR=1.98, 95% CI=1.13--3.48 for Trp allele) and 399 (OR=2.14, 95% CI=1.29--3.58 for Gln allele) and breast cancer risk. However, XRCC1 codon 280 genotype analysis showed no evidence for an association with increased risk of breast cancer. A combined analysis of the effect of XRCC1 codon 194 and 399 revealed the highest risk (OR=3.64, 95% CI=1.57--8.46) for carriers of the polymorphic alleles in both these codons. In conclusion, the present study suggested involvement of XRCC1 codon 194 and 399 polymorphisms in the genetic predisposition to breast cancer among South Indian women. Our preliminary results based on the analysis of functionally relevant polymorphisms in XRCC1 low penetrance gene may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer.     

Loss of heterozygosity in the RAD51 and BRCA2 regions in breast cancer

Background: Loss of heterozygosity (LOH) in the 15q14-21 and 13q12-13 regions can contribute to the inactivation of RAD51 and BRCA2 genes implicated in the pathogenesis of breast cancer. We investigated allelic losses in microsatellites in the RAD51 and BRCA2 regions, and their association with clinicopathological parameters in breast cancer. Methods: The LOH analysis was performed by amplifying DNA by PCR, using D15S118, D15S214, D15S1006 polymorphic markers in the 15q14-21 region and D13S260, D13S290 polymorphic markers in the 13q12-13 region in 36 sporadic breast cancer cases. Results: LOH in the RAD51 region ranged from 29% to 46% and in the BRCA2 region from 38% to 43% of informative cases. Eleven percent of the breast cancer cases displayed LOH for at least one studied marker in the RAD51 region exclusively. On the other hand, 44% of cases manifested statistically significant LOH for at least one microsatellite marker concomitantly in the RAD51 and BRCA2 regions. LOH in the RAD51 region similarly as in the BRCA2 region appeared to correlate with steroid receptors content and lymph node status. Discussion: The obtained results indicate that alteration in RAD51 region may contribute to the disturbances of DNA repair involving RAD51 and/or BRCA2 penetration and thus enhance the risk of breast cancer development.     

hOGG1 Ser326Cys polymorphism and breast cancer risk among Asian women

To evaluate the potential association between breast cancer risk and Ser ³²⁶ Cys polymorphism of hOGG1 gene, encoding for an enzyme involved in the base excision repair of 8-hydroxyguanine, hospital based case-control studies were conducted in two Asian populations consisting of 475 breast cancer cases (271 Korean and 204 Japanese) and 500 controls (314 Korean and 186 Japanese). PCR-based methods were employed for the genotyping analyses and the statistical evaluations were performed by unconditional logistic regression model. The frequency of hOGG1 Ser/Ser, Ser/Cys, and Cys/Cys genotypes were 22.5, 48.7, and 28.8% in all cases, and 23.7, 52.1, and 24.1% in the controls. No statistically significant associations between the genotypes and breast cancer risk were observed, neither when the ethnic groups were examined separately nor when the total study population was included. Neither did stratification by menopausal status reveal any association between hOGG1 genotypes and breast cancer. Our novel findings therefore suggest that hOGG1 Ser ³²⁶ Cys polymorphism is unlikely to play a modifying role in individual susceptibility to breast cancer among Asian women.     

<Emphasis Type="Italic">CCND1</Emphasis> G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis

Cyclin D1 (CCND1), a key cell cycle regulatory protein that governs the cell cycle progression from G1 to S phase, can promote cell proliferation or induce growth arrest and apoptosis. Since the identification of a well-characterized functional polymorphism, G870A in exon 4 of CCND1, several molecular epidemiological studies were conducted in recent years to evaluate the association between G870A and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 5,371 cases with breast cancer and 5,336 controls from 7 published case-control studies showed that the variant allele 870A was associated with a significantly increased risk of breast cancer (AA vs. GG: OR = 1.18, 95% CI = 1.06–1.32; AG vs. GG: OR = 1.12, 95% CI = 1.01–1.23; AA/AG vs. GG: OR = 1.14, 95% CI = 1.04–1.25) without any between-study heterogeneity. In the stratified analysis by race, we found that the increased breast cancer risk associated with G870A polymorphism was more evident in Caucasians (OR = 1.14, 95% CI = 1.01–1.28, P = 0.88 for heterogeneity test), but not significant in Asians (OR = 1.10, 95% CI = 0.85–1.42, P = 0.05 for heterogeneity test). The results suggest that CCND1 G870A polymorphism may contribute to breast cancer development, especially in Caucasians. Additional well-designed large studies were required for the validation of this association in different populations. Cheng Lu and Jing Dong contributed equally to this work.     

Polymorphisms of the <Emphasis Type="Italic">BRCA2</Emphasis> and <Emphasis Type="Italic">RAD51</Emphasis> Genes in Breast Cancer

Summary We performed a case-control study (150 cases and 150 controls) to test the association between three polymorphisms in BRCA2 and RAD51 genes and breast cancer risk. Genotypes were determined in DNA from blood cells by PCR–RFLP. Cancer occurrence was strongly associated with the BRCA2 Met/1915Thr homozygous polymorphic variants, whereas heterozygous variant was associated with significant reduction in breast cancer risk. Gene-gene interaction between the BRCA2-Met1915Thr Thr/Thr and BRCA2-Met784Val Met/Met homozygous variants increased the risk. Therefore, the Met1915Thr polymorphism in the BRCA2 gene may be considered as an independent marker of breast cancer.     

Biological significance of allele specific loss of the p53 gene in breast carcinomas

The p53 tumor suppressor gene has a central role in the defense against cancer, including breast cancer, and contains a polymorphic variant (Arg/Pro) at codon 72 that has been shown to have different biological properties regarding apoptosis and cell cycle arrest. Earlier studies have shown allele specific loss of heterozygosity (LOH) at this particular site and we aimed to investigate its biological relevance in codon 72 heterozygous breast cancer patients (i.e., survival and age of disease onset). 199 postmenopausal cases were analyzed for LOH using MegaBACE¹⁰⁰⁰ and statistics was performed using Statistical Package for Social Sciences. LOH was found in totally 124 (62.3%) patients and the Pro allele (n = 103) was significantly more often deleted compared to the Arg allele (n = 21) (P = 0.001). Patients with LOH of the Arg allele were diagnosed at an earlier age (mean age 62.5 years) than those with loss of the Pro allele (mean age 69.2 years) (P = 0.011). LOH of the Arg allele was also associated with worse survival (P = 0.05). LOH in comparison to ROH correlated significantly with increased S-phase fraction. Tumor size, stage or number of positive lymph nodes was not related to LOH. Our results and earlier findings suggest a selective loss of the Pro allele during carcinogenesis that might confer a growth advantage for cancer cells. On the other hand, it appears to be more harmful for patients to loose the Arg allele since we found that loss of this allele was associated with earlier onset and worse prognosis.     

Combined effect of GSTM1, GSTT1, and COMT genotypes in individual

Our previous studies suggested that both catechol O-methyl transferase (COMT) and glutathione S-transferase (GST) M1 and T1 genotypes are associated with breast cancer risk. Here we extended the studies to evaluate the potential combined effect of these genotypes in individual breast cancer risk. Incident breast cancer cases (n = 202) and controls (n = 299) with no previous cancer were recruited from three teaching hospitals in Seoul in 1996-1999. Information on putative risk factors was collected by interviewed questionnaire. PCR-based methods were used for the genotyping analyses. Odds ratios (ORs) and 95% confidence (CIs) intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Among pre-menopausal women the low activity associated (COMT *L) allele containing genotypes and the GSTM1 null genotype posed increased risks of breast cancer with ORs of 1.7 (95% CI = 1.0 - 2.8) and 1.7 (95% CI = 1.0-2.8), respectively. A marginally significant effect of GSTT1 null genotype was also observed when the total study population was considered (OR = 1.3, 95% CI = 1.0-2.1). When the combined genotype effects were examined, the concurrent lack of GSTM1 and GSTT1 genes posed a more than 2-fold risk of breast cancer (OR = 2.2, 95% CI = 1.2-3.9); this effect was mainly attributable in pre-menopausal women (OR = 3.2, 95% CI = 1.5-7.2). Moreover, the breast cancer risk increased in parallel with the number of COMT, GSTM1, and GSTT1 at-risk genotypes (p for trend = 0.003). This association was particularly clear in pre-menopausal women among whom combination of all three high-risk genotypes posed a 4.1-fold breast cancer risk (95% CI = 1.4-12.7) compared with pre-menopausal women without at-risk genotypes (p for trend = 0.001). The trend was more pronounced in women with BMI greater than 22 kg/m² (p for trend<0.001) and high-risk status of parity factor (nulliparous or women with the first full term pregnancy at age of over 25-year-old) (p for trend = 0.013). These results suggest the combined effect between reproductive factors and GSTM1, GSTT1 andCOMT genotypes in human breast carcinogenesis.     

Genetic variation in <Emphasis Type="Italic">IGF1</Emphasis>, <Emphasis Type="Italic">IGFBP3</Emphasis>, <Emphasis Type="Italic">IRS1</Emphasis>, <Emphasis Type="Italic">IRS2</Emphasis> and risk of breast cancer in women living in Southwestern United States

Background An insulin-related pathway to breast cancer has been hypothesized. Methods We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah. Results Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21–3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13–6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06–2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47–0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones. Conclusions Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.     

Genetic polymorphism in CYP17 and breast cancer risk in Japanese women

A case–control study was conducted to investigate the association of two genetic polymorphisms (1931T/C and 1951G/A) in the promoter region of the CYP17 gene with breast cancer risk in Japanese women. No significant association was observed between CYP17 polymorphism^1951G/A and breast cancer risk (odds ratio (OR)=1.71, 95% confidence interval (CI): 0.28–1.84). In contrast, a significant increase in breast cancer risk (OR=1.82, 95% CI: 1.07–3.12) was observed in CYP17^1931C/C homozygotes compared with CYP17^1931T/C heterozygotes and CYP17^1931T/T homozygotes when women aged 55 years were considered, but such a significant increase was not observed when women aged 54 years were considered (OR=0.96, 95% CI: 0.56–1.63). These results suggest that CYP17 polymorphism^1931T/C would be useful in the selection of Japanese women at a high risk for developing breast cancer at the age of 55 years.     

Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus

Population-based studies have reported significant associations between specific genetic polymorphisms and breast cancer susceptibility. A number of studies have demonstrated that common variants of genes involved in the DNA repair pathway act as low penetrance breast cancer susceptibility alleles. We aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the DNA repair genes XRCC1, XRCC2 and XRCC3 and breast cancer in MASTOS, a population-based case–control study of 1,109 Cypriot women with breast cancer diagnosed between 40 and 70 years and 1,177 age-matched healthy controls. Five coding SNPs were genotyped including rs1799782, rs25489 and rs25487 in XRCC1, rs3218536 in XRCC2 and rs861539 in XRCC3. Homozygous XRCC1 280His carriers had an increased risk of breast cancer (odds ratio 4.68; 95% CI 1.01–21.7; P = 0.03). The XRCC2 188His allele was associated with a marginal protective effect for breast cancer (odds ratio 0.79; 95% CI 0.62–1.00; P = 0.05). No significant associations were observed between the other three SNPs and breast cancer. This study suggests that genetic variation in SNPs in XRCC1 and XRCC2 genes may influence breast cancer susceptibility.     

Breast cancer risk and methylenetetrahydrofolate reductase polymorphism

Objective. Methylenetetrahydrofolate reductase (MTHFR), a polymorphic enzyme involved in folate metabolism, plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. Because breast-cell division occurs in women with active ovulatory cycles, polymorphisms in the MTHFR gene could be a risk factor for breast cancer. Methods. We genotyped 352 clinic-based study subjects for MTHFR, 105 subjects with breast cancer and 247 with benign breast disease, histopathologically classified as high-risk or low-risk for breast cancer. Questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. Results. Premenopausal women with the MTHFR polymorphism had a threefold increased breast cancer risk (OR = 2.8; 95%CI: 1.02–7.51) compared to the clinic-based controls with benign breast disease. Results were similar using either low- or high-risk controls. However, risk for postmenopausal women was not elevated (OR = 0.8; 95%CI 0.4–1.4). No significant interaction between genotype and smoking or alcohol was found, but polymorphic MTHFR decreased the likelihood of drinking alcohol (OR = 0.5; 95%CI 0.3–0.9). Conclusion. These data suggest that polymorphic MTHFR increases risk of premenopausal, but not postmenopausal, breast cancer. These findings should be explored with a larger sample size in order to analyze gene–environment interactions between MTHFR and folate. Once the intricate relationship between diet and breast cancer has been elucidated, new cancer control initiatives can be considered such as folate chemoprevention trials in high-risk individuals.     

The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified

To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese. Wen-Feng Li and Zhen Hu have contributed equally to this work.     

Analysis of <Emphasis Type="Italic">CHEK2</Emphasis> FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations

The CHEK2 gene mutations I157T (c.470T > C) and IVS2 + 1G > A affecting the forkhead-associated domain (FHA) have been shown to increase the risk of breast cancer development in several populations. We analyzed the CHEK2 gene segment coding for FHA domain in 673 unselected breast cancer patients and 683 controls from the Czech Republic using the denaturant high-performance liquid chromatography. The found frequency of predominant FHA alteration I157T did not differ between breast cancer patients (19/673; 2.82%) and controls (17/683; 2.49%; P = 0.71). Besides this mutation we characterized another nine alterations—six located within FHA coding sequence and three occurring in introns 1 or 2). Eight variants occurred once each in patients with breast cancer and two were present in controls. Three alterations found in breast cancer patients were novel missense variants (Y159H, T172A, and L174F) affecting highly conservative residues in FHA domain. Despite the lack of association of I157T mutation with breast cancer development in our population we deduced that the FHA domain is the subject of rare population-specific alterations that might modify risk of various cancers. Zdenek Kleibl, Ondrej Havranek contributed equally to this work.