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1.
《British journal of cancer》2009,101(12):2048-2054
Background:
In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:
We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.Results:
We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.Conclusion:
This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. 相似文献2.
Mulligan AM Couch FJ Barrowdale D Domchek SM Eccles D Nevanlinna H Ramus SJ Robson M Sherman M Spurdle AB Wappenschmidt B Lee A McGuffog L Healey S Sinilnikova OM Janavicius R Hansen Tv Nielsen FC Ejlertsen B Osorio A Muñoz-Repeto I Durán M Godino J Pertesi M Benítez J Peterlongo P Manoukian S Peissel B Zaffaroni D Cattaneo E Bonanni B Viel A Pasini B Papi L Ottini L Savarese A Bernard L Radice P Hamann U Verheus M Meijers-Heijboer HE Wijnen J Gómez García EB Nelen MR Kets CM Seynaeve C 《Breast cancer research : BCR》2011,13(6):R110
Introduction
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods
We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results
The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions
The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers. 相似文献3.
《British journal of cancer》2009,101(8):1456-1460
Background:
The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.Methods:
To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.Results:
No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.Conclusion:
There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. 相似文献4.
Osorio A Milne RL Alonso R Pita G Peterlongo P Teulé A Nathanson KL Domchek SM Rebbeck T Lasa A Konstantopoulou I Hogervorst FB Verhoef S van Dooren MF Jager A Ausems MG Aalfs CM van Asperen CJ Vreeswijk M Waisfisz Q Van Roozendaal CE Ligtenberg MJ;HEBON;EMBRACE Easton DF Peock S Cook M Oliver CT Frost D Curzon B Evans DG Lalloo F Eeles R Izatt L Davidson R Adlard J Eccles D Ong KR Douglas F Downing S Brewer C Walker L Nevanlinna H Aittomäki K Couch FJ Fredericksen Z Lindor NM Godwin A Isaacs C 《British journal of cancer》2011,104(8):1356-1361
Background:
Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2.Methods:
Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers.Results:
An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3–34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.Conclusions and inte
No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. 相似文献5.
Metcalfe K Gershman S Lynch HT Ghadirian P Tung N Kim-Sing C Olopade OI Domchek S McLennan J Eisen A Foulkes WD Rosen B Sun P Narod SA 《British journal of cancer》2011,104(9):1384-1392
Purpose:
The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk.Patients and methods:
Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.Results:
Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8% P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36% P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002).Conclusion:
The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation. 相似文献6.
《Breast cancer research : BCR》2015,17(1)
Introduction
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.Methods
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.Results
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.Conclusions
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users. 相似文献7.
Antoniou AC Shenton A Maher ER Watson E Woodward E Lalloo F Easton DF Evans DG 《Breast cancer research : BCR》2006,8(6):R72-6
Introduction
Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk.Methods
The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach.Results
Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers.Conclusion
The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers. 相似文献8.
S.A. Narod N. Tung J. Lubinski T. Huzarski M. Robson H.T. Lynch S.L. Neuhausen P. Ghadirian C. Kim–Sing P. Sun W.D. Foulkes and the Hereditary Breast Cancer Clinical Study Group 《Current oncology (Toronto, Ont.)》2014,21(2):64-68
Background
The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman’s reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers.Methods
We conducted a matched case–control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer.Results
After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001).Conclusions
In a woman with a BRCA1 or BRCA2 mutation who is diagnosed with breast cancer, the risk of cancer in the contralateral breast depends on the first diagnosis. That observation supports the hypothesis that there are important genetic or non-genetic modifiers of cancer risk in BRCA carriers. Discovering risk modifiers might lead to greater personalization of risk assessment and management recommendations for BRCA-positive patients. 相似文献9.
Laitman Y Kuchenbaecker KB Rantala J Hogervorst F Peock S Godwin AK Arason A Kirchhoff T Offit K Isaacs C Schmutzler RK Wappenschmidt B Nevanlinna H Chen X Chenevix-Trench G Healey S Couch F Peterlongo P Radice P Nathanson KL Caligo MA Neuhausen SL Ganz P Sinilnikova OM McGuffog L Easton DF Antoniou AC Wolf I Friedman E 《Breast cancer research and treatment》2012,132(3):1119-1126
Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. 相似文献
10.
Sidon L Ingham S Clancy T Clayton R Clarke A Jones EA Lalloo F Evans DG 《British journal of cancer》2012,106(4):775-779
Background:
Bilateral risk-reducing salpingo-oophorectomy (BRRSO) is the only effective way of reducing mortality from ovarian cancer. This study investigates uptake of BRRSO in 700 BRCA1/2 mutation carriers from Greater Manchester.Methods:
Dates of last follow-up and BRRSO were obtained, and the following variables were investigated: ovarian cancer risk/gene, age and breast cancer history. The date of the genetic mutation report was the initiation for Kaplan–Meier analysis.Results:
The uptake of BRRSO in BRCA1 mutation carriers was 54.5% (standard error 3.6%) at 5 years post testing compared with 45.5% (standard error 3.2%) in BRCA2 mutation carriers (P=0.045). The 40–59 years category showed the greatest uptake for BRRSO and uptake was significantly lower in the over 60 s (P<0.0001). Of the unaffected BRCA1 mutation carriers, 65% (standard error 5.1%) opted for surgery at 5 years post-testing compared with 41.1% (standard error 5.1%) in affected BRCA1 mutation carriers (P=0.045).Conclusion:
The uptake of BRRSO is lower in women previously affected by breast cancer and in older women. As there is no efficient method for early detection of ovarian cancer, uptake should ideally be greater. Counselling should be offered to ensure BRCA1/2 mutation carriers make an informed decision about managing their ovarian cancer risk. 相似文献11.
Walker LC Fredericksen ZS Wang X Tarrell R Pankratz VS Lindor NM Beesley J Healey S Chen X;kConFab Stoppa-Lyonnet D Tirapo C Giraud S Mazoyer S Muller D Fricker JP Delnatte C;GEMO Study Collaborators Schmutzler RK Wappenschmidt B Engel C Schönbuchner I Deissler H Meindl A Hogervorst FB Verheus M Hooning MJ van den Ouweland AM Nelen MR Ausems MG Aalfs CM van Asperen CJ Devilee P Gerrits MM Waisfisz Q;HEBON Szabo CI;ModSQuaD Easton DF Peock S Cook M Oliver CT Frost D Harrington P Evans DG 《Breast cancer research : BCR》2010,12(6):R102
Introduction
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.Methods
We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.Results
SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018).Conclusions
This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations. 相似文献12.
Ji Soo Park Seung-Tae Lee Jung Woo Han Tae Il Kim Eun Ji Nam Hyung Seok Park 《Clinical breast cancer》2018,18(5):362-373.e1
Introduction
We investigated the relative risk of breast and ovarian cancers related to the putative functional domain regions, obesity, and parity among Korean BRCA1/2 mutation carriers.Patients and Methods
We analyzed the clinical characteristics, cancer history, and mutations according to the putative functional domain of BRCA proteins among 229 women with BRCA1/2 mutations who were treated at Yonsei Cancer Center, Severance Hospital between January 2009 and March 2017.Results
Twenty-two carriers (18.8% of 117 BRCA1 mutation carriers) with mutations located in the BRCT domain region had a higher risk of breast cancers (hazard ratio [HR], 2.851; 95% confidence interval [CI], 1.614-5.039; P < .001) than those with mutations outside of the putative functional domains of BRCA1. The risk of ovarian cancer was increased in 13 (11.6%) of 112 BRCA2 mutation carriers, with mutations located on BRC repeat regions (HR, 3.129; 95% CI, 1.123-8.720; P = .029). The term-pregnancies number was a significant risk-reducing factor for breast cancers in BRCA1 mutation carriers (HR per pregnancy, 0.640; 95% CI, 0.508-0.806; P < .001), for breast cancers in BRCA2 mutation carriers (HR per pregnancy, 0.534; 95% CI, 0.419-0.681; P < .001), and for ovarian cancers for BRCA1 mutation carriers (HR per pregnancy, 0.625; 95% CI, 0.474-0.824; P = .001).Conclusion
Among Korean women with the BRCA1/2 mutation, the location of the mutations may influence the risk of breast and ovarian cancers according to the putative functional domain regions. Further investigations are required for risk prediction and preventive strategies in the BRCA1/2 mutation carriers. 相似文献13.
J Iqbal A Ragone J Lubinski H T Lynch P Moller P Ghadirian W D Foulkes S Armel A Eisen S L Neuhausen L Senter C F Singer P Ainsworth C Kim-Sing N Tung E Friedman M Llacuachaqui S Ping S A Narod the Hereditary Breast Cancer Study Group 《British journal of cancer》2012,107(12):2005-2009
Background:
Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation.Methods:
We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases.Results:
Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family.Conclusion:
The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies. 相似文献14.
《European journal of cancer (Oxford, England : 1990)》2015,51(16):2289-2295
Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC).In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs.By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p = 0.002) and rs445114 (p = 0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p = 0.011), rs614367/11q13.3 (p = 0.016) and rs1314913/14q24.1 (p < 0.0001).Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p = 0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p = 0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+ MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p = 0.041).In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers. 相似文献
15.
Tryggvadottir L Olafsdottir EJ Gudlaugsdottir S Thorlacius S Jonasson JG Tulinius H Eyfjord JE 《Breast cancer research : BCR》2003,5(5):R121-R128
Background
Germline mutations in the BRCA genes dramatically increase the risk of breast cancer. In the general population, breast cancer risk is affected by age at menarche, by age at first birth, by the number of births and by the duration of breast feeding. Whether this is true for mutation carriers is not clear.Methods
In a case–control study, nested in a population-based cohort of the Icelandic Cancer Detection Clinic, two groups of cases were defined, matched on year of birth, on age at diagnosis and on age when giving information on reproductive factors: 100 carriers of the Icelandic founder BRCA2 mutation 999del5, and 361 BRCA2-negative cases. The mean age at diagnosis was 48 years. There were 1000 women in a matched group of unaffected controls. Conditional logistic regression was used for the analysis.Results
An increased number of births was associated with a decreased risk of breast cancer in BRCA2-negative cases but not in BRCA2-positive cases. A negative association between risk and duration of breast feeding was observed only in the mutation carriers. These associations were not statistically significant, but the effects of the two variables differed significantly according to mutation status (P = 0.007 and P = 0.045 for interaction with number of births and with duration of breast feeding, respectively). This was maintained when limiting the analysis to women diagnosed older than the age of 40 years.Conclusion
The association between breast cancer and the number of pregnancies and between breast cancer and the duration of breast feeding was not the same for carriers and noncarriers of a detrimental BRCA2 mutation. In the context of other epidemiological and laboratory studies, this may indicate that the product of the BRCA2 gene has a function relating to the differentiation of epithelial tissue in the breast. 相似文献16.
Jakubowska A Rozkrut D Antoniou A Hamann U Scott RJ McGuffog L Healy S Sinilnikova OM Rennert G Lejbkowicz F Flugelman A Andrulis IL Glendon G Ozcelik H;OCGN Thomassen M Paligo M Aretini P;SWE-BRCA Kantala J Aroer B von Wachenfeldt A Liljegren A Loman N Herbst K Kristoffersson U Rosenquist R Karlsson P Stenmark-Askmalm M Melin B Nathanson KL Domchek SM Byrski T Huzarski T Gronwald J Menkiszak J Cybulski C Serrano P Osorio A Cajal TR Tsitlaidou M Benítez J Gilbert M;HEBON Rookus M Aalfs CM 《British journal of cancer》2012,106(12):2016-2024
Background:
The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.Methods:
To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.Results:
There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.Conclusion:
The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. 相似文献17.
Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers 总被引:1,自引:0,他引:1 下载免费PDF全文
Friedman E Kotsopoulos J Lubinski J Lynch HT Ghadirian P Neuhausen SL Isaacs C Weber B Foulkes WD Moller P Rosen B Kim-Sing C Gershoni-Baruch R Ainsworth P Daly M Tung N Eisen A Olopade OI Karlan B Saal HM Garber JE Rennert G Gilchrist D Eng C Offit K Osborne M Sun P Narod SA;Hereditary Breast Cancer Clinical Study Group 《Breast cancer research : BCR》2006,8(2):R15-7
Introduction
BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date.Methods
In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer.Results
There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16–0.83; p = 0.02).Conclusion
Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers. 相似文献18.
Xuan-Anh Phi Sepideh Saadatmand Geertruida H De Bock Ellen Warner Francesco Sardanelli Martin O Leach Christopher C Riedl Isabelle Trop Maartje J Hooning Rodica Mandel Filippo Santoro Gek Kwan-Lim Thomas H Helbich Madeleine MA Tilanus-Linthorst Edwin R van den Heuvel Nehmat Houssami 《British journal of cancer》2016,114(6):631-637
Background:
We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials.Methods:
Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated.Results:
In BRCA1/2 mutation carriers of all ages (BRCA1=1219 and BRCA2=732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P>0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening.Conclusions:
Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering. 相似文献19.
Bordeleau L Lipscombe L Lubinski J Ghadirian P Foulkes WD Neuhausen S Ainsworth P Pollak M Sun P Narod SA;Hereditary Breast Cancer Clinical Study Group 《Cancer》2011,117(9):1812-1818
BACKGROUND:
Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.METHODS:
The authors reviewed the medical histories of 6052 women with a BRCA1 or BRCA2 mutation, half of whom had been diagnosed with breast cancer. They estimated the odds ratio for breast cancer, given a self‐report of diabetes. They then estimated the hazard ratio for a new diagnosis of diabetes associated with a history of breast cancer.RESULTS:
There was no excess of diabetes in the period before the diagnosis of breast cancer, compared with controls with no diagnosis of breast cancer. The risk of diabetes was doubled among BRCA carriers in the 15‐year period after the diagnosis of breast cancer (relative risk, 2.0; 95% confidence interval [CI], 1.4‐2.8; P = .0001), compared with carriers without cancer. The risk was particularly high for women with a body mass index (BMI) >25.0 kg/m2 (odds ratio, 5.8; 95% CI, 4.0‐8.6; P = .0001).CONCLUSIONS:
After a diagnosis of breast cancer, women with a BRCA1 or BRCA2 mutation face a 2‐fold increase in the risk of diabetes, which is exacerbated by a high BMI. Cancer 2011. © 2010 American Cancer Society. 相似文献20.
C M Phelan J Iqbal H T Lynch J Lubinski J Gronwald P Moller P Ghadirian W D Foulkes S Armel A Eisen S L Neuhausen L Senter C F Singer P Ainsworth C Kim-Sing N Tung M Llacuachaqui G Chornokur S Ping S A Narod the Hereditary Breast Cancer Study Group 《British journal of cancer》2014,110(2):530-534