Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population

Inability to correctly repair DNA damage is known to play a role in the development of breast cancer. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been identified, which modify the DNA repair capacity, which in turn may affect the risk of developing breast cancer. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 62 SNPs in 29 genes in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. Five SNPs were associated with breast cancer. SNPs rs13312840 and rs769416 in the NBS1 gene were associated with a decrease in breast cancer risk (OR TT vs. TC/CC = 0.58; 95% CI, 0.37–0.92; P = 0.019 and OR GG vs. GT/TT = 0.23, 95% CI 0.06–0.85, P = 0.017, respectively). The variant allele of MRE11A rs556477 was also associated with a reduced risk of developing the disease (OR AA vs. AG/GG = 0.76; 95% CI, 0.64–0.91; P = 0.0022). MUS81 rs545500 and PBOV1 rs6927706 SNPs were associated with an increased risk of developing breast cancer (OR GG vs. GC/CC = 1.21, 95% CI, 1.02–1.45; P = 0.031; OR AA vs. AG/GG = 1.53, 95% CI, 1.07–2.18; P = 0.019, respectively). Finally, haplotype-based tests identified significant associations between specific haplotypes in MRE11A and NBS1 genes and breast cancer risk. Further large-scale studies are needed to confirm these results.     

Variation in genes required for normal mitosis and risk of breast cancer

The down-regulation of genes involved in normal cell division can cause aberrant mitoses and increased cell death. Surviving cells exhibit aneuploidy and/or polyploidy. Since mitotic disruption has been linked with tumor development and progression, alterations in the expression or activity of these mitotic regulators may contribute to breast tumor formation. We evaluated associations between common inherited variation in these genes and breast cancer risk. Two hundred and five tagging and candidate functional single nucleotide polymorphisms in 30 genes required for normal cell division were genotyped in 798 breast cancer cases and 843 controls from the Mayo Clinic breast cancer study. Two variants in EIF3A (rs10787899 and rs3824830; P < 0.01) and four variants in SART1 (rs660118, rs679581, rs754532, and rs735942; P _trend ≤ 0.02) were significantly associated with an altered risk of breast cancer along with single variants in RRM2, PSCD3, C11orf51, CDC16, SNW1, MFAP1, and CDC2 (P < 0.05). Variation in both SART1 (P = 0.009) and EIF3A (P = 0.02) was also significant at the gene level. Analyses suggested that SART1 SNPs rs660118 and rs679581 accounted for the majority of the association of that gene with breast cancer. The observed associations between breast cancer risk and genetic variation in the SART1 and EIF3A genes that are required for maintenance of normal mitosis suggest a direct role for these genes in the development of breast cancer.     

Low penetrance breast cancer predisposition SNPs are site specific

Large scale association studies have identified low penetrance susceptibility alleles that predispose to breast cancer. A locus on chromosome 8q24.21 has been shown to harbour variants that predispose to breast, ovarian, colorectal and prostate cancer. The finding of risk variants clustering at 8q24 suggests that there may be common susceptibility alleles that predispose to more than one epithelial cancer. The aim of this study was firstly to determine whether previously identified breast cancer susceptibility alleles are associated with sporadic breast cancer in the West of Ireland and secondly to ascertain whether there are susceptibility alleles that predispose to all three common epithelial cancers (breast, prostate, colon). We genotyped a panel of 24 SNPs that have recently been shown to predispose to prostate, colorectal or breast cancer in 988 sporadic breast cancer cases and 1,016 controls from the West of Ireland. We then combined our data with publicly available datasets using standard techniques of meta-analysis. The known breast cancer SNPs rs13281615, rs2981582 and rs3803662 were confirmed as associated with breast cancer risk (P _{allelic test} = 1.8 × 10⁻², OR = 1.17; P _{allelic test} = 2.2 × 10⁻³, OR = 1.22; P _{allelic test} = 5.1 × 10⁻², OR = 1.15, respectively) in the West of Ireland cohort. For the remaining five breast cancer SNPs that were studied there was no evidence of an association with breast cancer in the West Ireland population (P _{allelic test} > 6.5 × 10⁻²). There was also no association between any of the prostate or colorectal susceptibility SNPs, whether at 8q24 or elsewhere, with breast cancer risk. Meta-analysis confirmed that all susceptibility SNPs were site specific, with the exception of rs6983269 which is known to predispose to both colorectal and prostate cancer. This study confirms that susceptibility loci at FGFR2, 8q24 and TNCR9 predispose to sporadic breast cancer in the West of Ireland. It also suggests that low penetrance susceptibility SNPs for breast, prostate and colorectal cancer are distinct. Although 8q24 harbours variants that predispose to all three cancers, the susceptibility loci within the region appear to be specific for the different cancer types with the exception of rs6983269 in colon and prostate cancer. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

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.     

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 variants in trinucleotide repeat-containing 9 (TNRC9) are associated with risk of estrogen receptor positive breast cancer in a Chinese population

Trinucleotide repeat-containing 9 (TNRC9), a high mobility group chromatin-associated protein, has been implicated in breast cancer metastasis to the bone. Recently, several single nucleotide polymorphisms (SNPs) of TNRC9 were identified as novel breast cancer susceptibility loci by whole genome association studies, especially in estrogen receptor (ER) positive tumors. In the present case–control study of 1,049 breast cancer patients and 1,073 cancer-free controls in a Chinese population, we genotyped three polymorphisms (rs3803662C/T, rs12443621A/G, and rs8051542C/T) of the TNRC9 gene using the SNPstream 12-plex platform to test the hypothesis that these SNPs are associated with breast cancer risk in this population. None of the three polymorphisms was significantly associated with breast cancer risk in the whole data set (P = 0.151, 0.644, and 0.737 for rs3803662, rs12443621. and rs8051542, respectively). However, rs12443621 AG/GG genotypes were significantly associated with increased risk of ER positive breast cancer (OR = 1.38, 95% CI = 1.01–1.88), compared with homozygote AA. In addition, a borderline significantly increased risk was also observed for the variant genotypes (CT/TT) of rs8051542 C/T compared with the wild-type genotype (CC) (adjusted OR = 1.26, 95% CI = 0.99–1.60). Interestingly, a significant interaction was detected between rs12443621A/G and ER status on breast cancer risk in a case-only analysis (P for interaction = 0.004). These findings suggest that genetic variants of TNRC9 may contribute to the development of ER positive breast cancer.     

Vitamin D receptor variants and breast cancer risk in the Polish population

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33–2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71–3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.     

Risk of aggressive breast cancer in women of Han nationality carrying TGFB1 rs1982073 C allele and FGFR2 rs1219648 G allele in North China

The high morbidity and aggressive behavior of breast cancer are associated with genetic variations. Single nucleotide polymorphisms (SNPs) in many genes have been demonstrated as a risk factor for breast cancer. In this study, we evaluated the association of the SNP rs1982073 (Leu10Pro) in transforming growth factor-beta 1 (TGFB1) gene and the SNP rs1219648 in fibroblast growth factor receptor 2 (FGFR2) gene with the risk and aggressiveness of breast cancer among women of Han nationality in North China. TaqMan allelic discrimination assay was performed to genotype rs1982073 and rs1219648 in 447 breast cancer cases and 406 age-matched healthy controls. The results imply that genotype frequencies of rs1982073 and rs1219648 were not significantly different between breast cancer patients and healthy controls. However, for TGFB1 SNP rs1982073, the C-carriers (T/C+C/C genotype) were more likely to bear tumors of greater aggressiveness (histological grade III) than T/T-carriers (grade I–II) (OR = 3.45, 95% CI: 1.48–8.00, P = 0.004). For FGFR2 SNP rs1219648, G-carriers (A/G+G/G genotype) were more significantly linked to tumors with lymph node metastasis than those with A/A genotype (lymph node negative) (OR = 1.69, 95% CI: 1.11–2.58, P = 0.016). Therefore, the SNPs of TGFB1 rs1982073 and FGFR2 rs1219648 may contribute to the identification of patients with more aggressive breast cancers among Han women in North China.     

Melatonin pathway genes and breast cancer risk among Chinese women

Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-stage analysis of genome-wide association data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPs were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR = 0.78, 95% CI = 0.62–0.97, P = 0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (P-value for interaction = 0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer compared with major allele carriers (TT or TG) (OR = 1.57, 95% CI = 1.07–2.31, P = 0.020), while postmenopausal women were at decreased risk (OR = 0.58, 95% 0.36–0.95, P = 0.030). No significant breast cancer associations were found for variants in the AANAT gene. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequilibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin and glucose family members, further research may focus on clarifying this relationship.     

Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case–control study in Thai women

Dietary folate as well as polymorphic variants in one-carbon metabolism genes may modulate risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and repair. Alcohol is well recognized as a risk factor for breast cancer, and interactions with one-carbon metabolism has also been suggested. The purpose of this study is to test the hypothesis that genetic polymorphisms in the folate and alcohol metabolic pathway are associated with breast cancer risk. Twenty-seven single nucleotide polymorphisms (SNPs) in the MTR, MTRR, MTHFR, TYMS, ADH1C, ALDH2, GSTP1, NAT1, NAT2, CYP2E1 DRD2, DRD3, and SLC6A4 were genotyped. Five hundred and seventy patients with histopathogically confirmed breast cancer and 497 controls were included in the present study. Association of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (95% CI). Increased risk was observed for homozygotes at the MTR SNPs (rs1770449 and rs1050993) with the OR = 2.21 (95% CI 1.18–4.16) and OR = 2.24 (95% CI 1.19–4.22), respectively. A stratified analysis by menopausal status indicated the association between the NAT2 SNP (rs1799930) and breast cancer was mainly evident in premenopausal women (OR 2.70, 95% CI 1.20–6.07), while the MTRR SNP (rs162049) was significant in postmenopausal women (OR 1.61, 95% CI 1.07–2.44). Furthermore, SNPs of the genes that contribute to alcohol behavior, DRD3 (rs167770), DRD2 (rs10891556), and SLC6A4 (rs140701), were also associated with an increased risk of breast cancer. No gene–gene or gene–environment interactions were observed in this study. Our results suggest that genetic polymorphisms in folate and alcohol metabolic pathway influence the risk of breast cancer in Thai population.     

Association of diagnostic work-up with subsequent attendance in a breast cancer screening program for false-positive cases

Centrosome amplification has been detected in premalignant lesions and in situ tumors in the breast and in over 70% of invasive breast tumors, and has been associated with aneuploidy and tumor development. Based on these observations, the contribution of commonly inherited genetic variation in candidate genes related to centrosome structure and function to breast cancer risk was evaluated in an association study. Seven-hundred and 82 single nucleotide polymorphisms (SNPs) from 101 centrosomal genes were analyzed in 798 breast cancer cases and 843 controls from the Mayo Clinic Breast Cancer Study to assess the association between these SNPs (both individually and combined) and risk of breast cancer in this population. Eleven SNPs out of 782 from six genes displayed associations with breast cancer risk (P < 0.01). Haplotypes in five genes also displayed significant associations with risk. A two SNP combination of rs10145182 in NIN and rs2134808 in the TUBG1 locus (P-interaction = 0.00001), suggested SNPs in mediators of microtubule nucleation from the centrosome contribute to breast cancer. Evaluation of the simultaneous significance of all SNPs in the centrosome pathway suggested that the centrosome pathway is highly enriched (P = 4.76 × 10⁻⁵⁰) for SNPs that are associated with breast cancer risk. Collections of weakly associated genetic variants in the centrosome pathway, rather than individual highly significantly associated SNPs, may account for a putative role for the centrosome pathway in predisposition to breast cancer.     

Potentially functional polymorphisms in DNA repair genes and non-small-cell lung cancer survival: a pathway-based analysis

To assess systematically whether potentially functional polymorphisms in DNA repair genes influence the clinical behavior of non‐small‐cell lung cancer (NSCLC), we examined the impact of a comprehensive panel of 218 signal nucleotide polymorphisms (SNP) in 50 candidate DNA repair genes on overall survival of NSCLC in a case‐cohort of 568 lung cancer patients. SNPs associated with lung cancer prognosis primarily mapped to 14 genes in different repair pathways, and 6 SNPs were remained in the final model after multivariate stepwise Cox regression analysis: ATM rs189037; MRE11A rs11020802; ERCC2 rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933. In the combined analysis of these 6 SNPs, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend: <0.0001) and patients having 2–4 unfavorable loci had a 1.99‐fold elevated risk of death 95% confidence interval (CI) = 1.58–2.50, compared with those carrying 0–1 unfavorable loci, and this elevated risk was more evident among stages I–II patients (hazard ratio = 3.04, 95% CI = 1.86–4.98, P for heterogeneity: 0.07). Furthermore, a significant effect of SNPs in nucleotide excision repair pathway on lung cancer survival was observed among 185 stages III–IV patients treated with platinum‐based chemotherapy without surgical operation: XPC rs2228000 (Ala499Val; P = 0.002) and ERCC1 rs11615 (Asn118Asn; P = 0.012). Our data indicate that potentially functional polymorphisms in DNA repair genes may serve as candidate prognostic markers of clinical outcome of NSCLC. © 2011 Wiley Periodicals, Inc.     

Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases

Background Around half of familial breast cancer cases are caused by germ-line mutations in genes which are critically involved in the maintenance of genome stability. Mutations in related genes functioning in DNA repair may account for currently unattributed cases. Two such genes, RAP80 and Abraxas, have recently been identified to be in a complex with BRCA1, and are required for the localization of BRCA1 to DNA damage foci. Methods RAP80 and Abraxas variants were screened for in a cohort of 95 high risk, non-BRCA1/2 breast cancer cases of varying ethnicity: those of Ashkenazi Jewish (n = 35), mixed Canadian (n = 34) and Swiss descent (n = 26). Results We have identified four missense variants, four silent SNPs, three SNPs in the UTRs and seven intronic variants in RAP80. Two of the previously reported RAP80 variants were further investigated. In Abraxas, we have identified two missense, nine intronic and two variants in the 3′ UTR. Conclusions Overall, it seems unlikely that moderate to highly penetrant alleles of either RAP80 or Abraxas, confer a significantly high relative risk of breast cancer.     

IGF1 htSNPs in relation to IGF-1 levels in young women from high-risk breast cancer families: implications for early-onset breast cancer

High levels of insulin-like growth factor-1 (IGF-1) have been associated with increased risk of developing several types of cancer including breast cancer. A set of nine haplotype tagging SNPs (htSNPs) in the IGF1 gene were associated with IGF-1 levels and prostate cancer in a Swedish population. We aimed to study the nine htSNPs in three haplotype blocks (block1: rs855211, rs35765, rs2162679; block2: rs1019731, rs7956547, rs5742632; and block3 rs2033178, rs7136446, rs6220) combined into diplotypes, and three additional SNPs (rs5742612, rs35765817, rs35455143) in relation to IGF-1 levels, BRCA status, the IGF1 CA-repeat microsatellite, and breast cancer in a population of 325 Swedish women from breast cancer high-risk families. Questionnaire data and blood samples for IGF-1 and genetic analyses were obtained twice during the menstrual cycle from 269 women aged 40 years or younger. SNP analyses were also performed in 56 BRCA1/2 mutation carriers. Women (n = 14) with any rare variant block1 diplotype had higher odds to be BRCA1 mutation carriers OR 4.1 (95% CI 1.4–12.2), to lack the common IGF1 19 CA-repeat allele OR 33.3 (95% CI 6.6–166.7), and were more likely to develop early-onset breast cancer (Log Rank P < 0.001) than women with common block1 diplotypes. In the subgroup of BRCA1 mutation carriers, block1 rare diplotypes were associated with earlier diagnosis (Log Rank P = 0.031). No association was found between IGF-1 levels and individual SNPs or diplotypes. If confirmed, these rare diplotypes may identify women with particularly high risk for early-onset breast cancer and this group should be included in forthcoming studies.     

IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families

The insulin-like growth factor (IGF) pathway has been implicated as risk modifier in premenopausal breast cancer. In this study, associations between single nucleotide polymorphisms (SNPs) and diplotypes in the IGFBP1 and IGFBP3 genes and circulating IGFBP-3 levels, BRCA family status and breast cancer among women from high-risk breast cancer families were investigated. Nine IGFBP1 and IGFBP3 SNPs were genotyped with PCR-based methods in 323 women. Nine IGFBP1 and ten IGFBP3 diplotypes were identified. Plasma IGFBP-3 levels obtained during cycle day 18–23 were available for 231 women, 87 current users of combined oral contraceptives and 144 non-users. IGFBP1 (rs1995051 and rs4988515) and IGFBP3 (rs2471551 and rs2854744) SNPs were associated with circulating IGFBP-3 levels (P < 0.05). IGFBP1 ^low diplotypes were associated with lower IGFBP-3 levels and were more common in BRCA2 families OR 2.05 (95%CI 0.97–4.30). IGFBP3 ^high diplotypes were associated with higher IGFBP-3 levels and were more common in BRCAX families OR 1.68 (95%CI 1.04–2.74). After adjusting the models for BRCA family status, both the BRCA1 and BRCA2 family status (P ≤ 0.006) and the IGFBP1 diplotype GTAC/ACAT (P = 0.004) were associated with lower IGFBP-3 levels. Similarly, both the BRCA1 and BRCA2 family status (P ≤ 0.03) and the IGFBP-3 diplotypes GCA/GCG (P = 0.007) and GCG/CCG (P = 0.002) were significantly associated with lower IGFBP-3 levels, adjusted for age, weight, OC use, and other IGFBP diplotypes. No individual SNP was associated with breast cancer. There were 23 cases of breast cancer and one IGFBP1 diplotype was associated with a decreased risk of breast cancer after age 18 (log rank P=0.05). In conclusion, independent effects from IGFBP1, IGFBP3 diplotypes, and BRCA family status on IGFBP-3 levels were observed. These factors may influence the risk of breast cancer among women from high-risk breast cancer families.     

Polymorphisms in DNA repair and apoptosis-related genes and clinical outcomes of patients with non-small cell lung cancer treated with first-line paclitaxel-cisplatin chemotherapy

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNPs) in genes in DNA repair and apoptosis pathways and determine the relationship between polymorphisms and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with first-line paclitaxel-cisplatin chemotherapy. Three hundred eighty two patients with NSCLC were enrolled. Seventy-four SNPs in 48 genes (42 SNPs in 27 DNA repair pathway genes and 32 SNPs in 21 apoptotic pathway genes) were genotyped and their associations with chemotherapy response and overall survival (OS) were analyzed. Among SNPs in DNA repair genes, BRCA1 rs799917 was significantly associated with both chemotherapy response and OS. XRCC1 rs25487 exhibited a significant association with chemotherapy response and ERCC2 rs1052555 with OS. Four SNPs in apoptotic genes (TNFRSF1B rs1061624, BCL2 rs2279115, BIRC5 rs9904341, and CASP8 rs3769818) were significantly associated with OS, but not with response to chemotherapy. When the six SNPs which were associated with OS in individual analysis were combined, OS decreased as the number of bad genotypes increased (P_trend = 2 × 10⁻⁶). Patients with 3, and 4–6 bad genotypes had significantly worse OS compared with those carrying 0–2 bad genotypes (adjusted hazard ratio [aHR] = 1.54, 95% CI = 1.14–2.08, P = 0.005; aHR = 2.10, 95% CI = 1.55–2.85, P = 2 × 10⁻⁶, respectively). In conclusion, these findings suggest that the six SNPs identified, particularly their combined genotypes, could be used as biomarkers predicting chemotherapy response and survival of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.     

A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women

RecQ helicases play a central role in maintaining genome stability and may interact with some important cancer-related proteins such as BRCA1. Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature aging and cancer predisposition, including breast cancer. In this case–control study of 1,004 breast cancer cases and 1,008 controls, we tested the hypothesis that non-conservative amino acid exchanges in WRN (leu1074Phe), BLM (Met298Thr) and BRCA1 (Pro871Leu) are independently or jointly associated with the risk of breast cancer in Chinese women. We found that the variant genotype of WRN Leu1074Phe was associated with a 1.36-fold significantly increased risk of breast cancer (OR = 1.36, 95% CI = 1.06–1.74). Moreover, a significant gene–environment interaction was evident between WRN leu1074Phe and age at menarche (P _int = 0.02). Subjects carrying Phe/Phe genotype and with earlier age at menarche had 3.58-fold increased risk of breast cancer (OR = 3.58, 95% CI = 2.54–5.05). However, we did not find the significant main effect of polymorphisms in BLM and BRCA1 and also no locus–locus interactions were identified between WRN, BLM and BRCA1. These findings indicate that WRN leu1074Phe variant may contribute to the susceptibility of breast cancer in Chinese women.     

Germline mutation in DNA‐repair genes is associated with poor survival in BRCA1/2‐negative breast cancer patients

BRCA1/2 genes are the most frequently germline mutated DNA‐repair genes, and the survival of BRCA1/2 carriers has been extensively explored in breast cancer. However, the prevalence of germline mutations in non‐BRCA1/2 DNA‐repair genes and the survival of carriers are largely unknown in a large cohort of unselected breast cancer patients. Germline mutations in 16 DNA‐repair genes were determined using a multigene panel in 7657 BRCA1/2‐negative breast cancer patients who were unselected for family history of cancer or age at diagnosis. Among the 7657 BRCA1/2‐negative breast cancer patients, 257 (3.4%) carried at least 1 pathogenic germline mutation in the 16 DNA‐repair genes. The prevalence of DNA‐repair gene mutations was significantly higher in familial breast cancers (5.2%, P = 0.002) and early‐onset breast cancers (diagnosed at and before the age of 40) (4.5%, P = 0.003) than that of sporadic breast cancers (2.9%) (diagnosed above age of 40), respectively. The DNA‐repair gene mutation carriers were significantly more likely to have a larger tumor (P = 0.04) and axillary lymph node metastasis (P = 0.03). Moreover, DNA‐repair gene mutation was an independent unfavorable factor for recurrence‐free survival (adjusted hazard ratio [HR] = 1.38, 95% CI: 1.00‐1.91, P = 0.05) and disease‐specific survival (adjusted HR=1.63, 95% CI: 1.04‐2.57, P = 0.03) in this cohort. Overall, 3.4% of BRCA1/2‐negative breast cancer patients carried germline mutations in the 16 DNA‐repair genes, and the DNA‐repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers.     

Germline RAP80 mutations and susceptibility to breast cancer

Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5′UTR (c.-8A > G) and a variant in the 3′UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2–5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.