Breast cancer susceptibility variants alter risks in familial disease

Latif, Ayşe; Hadfield, Kristen D.; Roberts, Stephen A.; Shenton, Andrew; Lalloo, Fiona; Black, Graeme C M; Howell, Anthony; Evans, D. Gareth; Newman, William G.

doi:10.1136/jmg.2009.067256

Cited by 36 publications

(46 citation statements)

References 25 publications

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“…We had already validated seven gene variants previously associated with increased breast cancer risk (BARD1, TOX3, FGFR2, MAP3K1, LSP1, CASP8 and 8q) in ≈200 female BRCA1 and ≈200 BRCA2 carriers, confirming increased risk of breast cancer conferred by variants in FGFR2 and TOX3 and the protective effect of the minority allele in CASP8 in BRCA1/BRCA2-positive individuals. 135 We proposed to extend our analysis to include all female carriers (n = 850 at that time) and assess the variants for interactions and modifier effects. New variants were proposed to be added as they were identified.…”

Section: Methodsmentioning

confidence: 99%

“…141 The outcome measure was the 10-year RR of developing breast cancer. Histograms are shown in Figure 18 for the TC model, the SNP score using 18 genes previously published 141 but with risks updated from Latif et al, 135 the full set of 67 SNPs, and a combined TC + SNP67 distribution assuming independence. Initial evaluations have shown that the TC model and SNP18 scores appear to be independent.…”

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confidence: 99%

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Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

Evans

Astley

Stavrinos³

et al. 2016

Programme Grants Appl Res

118

126

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BackgroundIn the UK, women are invited for 3-yearly mammography screening, through the NHS Breast Screening Programme (NHSBSP), from the ages of 47–50 years to the ages of 69–73 years. Women with family histories of breast cancer can, from the age of 40 years, obtain enhanced surveillance and, in exceptionally high-risk cases, magnetic resonance imaging. However, no NHSBSP risk assessment is undertaken. Risk prediction models are able to categorise women by risk using known risk factors, although accurate individual risk prediction remains elusive. The identification of mammographic breast density (MD) and common genetic risk variants [single nucleotide polymorphisms (SNPs)] has presaged the improved precision of risk models.ObjectivesTo (1) identify the best performing model to assess breast cancer risk in family history clinic (FHC) and population settings; (2) use information from MD/SNPs to improve risk prediction; (3) assess the acceptability and feasibility of offering risk assessment in the NHSBSP; and (4) identify the incremental costs and benefits of risk stratified screening in a preliminary cost-effectiveness analysis.DesignTwo cohort studies assessing breast cancer incidence.SettingHigh-risk FHC and the NHSBSP Greater Manchester, UK.ParticipantsA total of 10,000 women aged 20–79 years [Family History Risk Study (FH-Risk); UK Clinical Research Network identification number (UKCRN-ID) 8611] and 53,000 women from the NHSBSP [aged 46–73 years; Predicting the Risk of Cancer At Screening (PROCAS) study; UKCRN-ID 8080].InterventionsQuestionnaires collected standard risk information, and mammograms were assessed for breast density by a number of techniques. All FH-Risk and 10,000 PROCAS participants participated in deoxyribonucleic acid (DNA) studies. The risk prediction models Manual method, Tyrer–Cuzick (TC), BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) and Gail were used to assess risk, with modelling based on MD and SNPs. A preliminary model-based cost-effectiveness analysis of risk stratified screening was conducted.Main outcome measuresBreast cancer incidence.Data sourcesThe NHSBSP; cancer registration.ResultsA total of 446 women developed incident breast cancers in FH-Risk in 97,958 years of follow-up. All risk models accurately stratified women into risk categories. TC had better risk precision than Gail, and BOADICEA accurately predicted risk in the 6268 single probands. The Manual model was also accurate in the whole cohort. In PROCAS, TC had better risk precision than Gail [area under the curve (AUC) 0.58 vs. 0.54], identifying 547 prospective breast cancers. The addition of SNPs in the FH-Risk case–control study improved risk precision but was not useful inBRCA1(breast cancer 1 gene) families. Risk modelling of SNPs in PROCAS showed an incremental improvement from using SNP18 used in PROCAS to SNP67. MD measured by visual assessment score provided better risk stratification than automatic measures, despite wide intra- and inter-reader variability. Using a MD-adjusted TC model in PROCAS improved risk stratification (AUC = 0.6) and identified significantly higher rates (4.7 per 10,000 vs. 1.3 per 10,000;p < 0.001) of high-stage cancers in women with above-average breast cancer risks. It is not possible to provide estimates of the incremental costs and benefits of risk stratified screening because of lack of data inputs for key parameters in the model-based cost-effectiveness analysis.ConclusionsRisk precision can be improved by using DNA and MD, and can potentially be used to stratify NHSBSP screening. It may also identify those at greater risk of high-stage cancers for enhanced screening. The cost-effectiveness of risk stratified screening is currently associated with extensive uncertainty. Additional research is needed to identify data needed for key inputs into model-based cost-effectiveness analyses to identify the impact on health-care resource use and patient benefits.Future workA pilot of real-time NHSBSP risk prediction to identify women for chemoprevention and enhanced screening is required.FundingThe National Institute for Health Research Programme Grants for Applied Research programme. The DNA saliva collection for SNP analysis for PROCAS was funded by the Genesis Breast Cancer Prevention Appeal.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

Evans

Astley

Stavrinos³

et al. 2016

Programme Grants Appl Res

118

126

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“…In total, 18 studies involving 44,820 cases and 58,316 controls met the inclusion criteria and were used in pooled analyses (Antoniou et al, 2008;Garcia-Closas et al, 2008;Li et al, 2009;Mcinerney et al, 2009;Gorodnova et al, 2010;Latif et al, 2010;Liang et al, 2010;Tamimi et al, 2010;Campa et al, 2011;Han et al, 2011;Slattery et al, 2011;Harlid et al, 2012;Shan et al, 2012;Mizoo et al, 2013;Ottini et al, 2013;Chen et al, 2014;Elematore et al, 2014). The primary features of these investigations are shown in Table 1.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…In addition to the well-defined, highly penetrant modifications to genes such as BRCA1 and BRCA2, which are only observed in a limited number of cases, certain common, low-penetrance variations have been identified in other genes potentially implicated in BC (Dong et al, 2008). Recently, several genome-wide association studies (GWAS; Antoniou et al, 2008;Garcia-Closas et al, 2008;Mcinerney et al, 2009;Latif et al, 2010) have revealed multiple BC-associated loci, of which the majority are single nucleotide polymorphisms (SNPs). However, these contribute only insignificant effects to BC risk.…”

Section: Introductionmentioning

confidence: 99%

Increased risk of breast cancer in individuals carrying the TNRC9 rs3803662 C>T polymorphism: a meta-analysis of case-control studies

Wang

Cao

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Currently, the relationship between the trinucleotide repeat containing 9 (TNRC9) rs3803662 C>T polymorphism and risk of breast cancer (BC) is uncertain. Here, we attempted to obtain a more accurate assessment of this association by conducting a meta-analysis of all eligible case-control investigations, comprising 44,820 cases and 58,316 controls. A comprehensive search was performed to identify all suitable studies involving the TNRC9 rs3803662 polymorphism and BC risk. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated using fixed-or random-effect models. Heterogeneity, publication bias, and sensitivity analyses were also carried out. We found that the variant T allele of rs3803662 C>T greatly increases BC risk (CT vs CC: OR = 1.14, 95%CI = 1.07-1.22, P < 0.001; TT vs CC: OR = 1.38, 95%CI = 1.25-1.53, P < 0.001; CT/TT vs CC: OR = 1.19, 95%CI = 1.11-1.28, P < 0.001; TT vs CT/CC: OR = 1.28, 95%CI = 1.19-1.38, P < 0.001). Stratified analysis based on ethnicity also revealed a markedly increased risk in Asian and Caucasian populations. Moreover, studies with hospital-based control groups showed elevated risk under the four genetic models employed, as did those using population-based controls, except under heterozygote comparison. The TNRC9 rs3803662 C>T polymorphism is greatly related to increased risk of BC, in both Asian and Caucasian populations.

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“…In addition to the BRCA1/2 mutation analysis, women were genotyped for 18 SNPs that have been shown to be associated with breast cancer risk in the general population (7) and a subset of SNPs in familial breast cancer (18). Using the published per SNP ORs and risk-allele frequencies (RAF) from Turnbull and colleagues (e.g.…”

Section: Dna Testing For Snpsmentioning

confidence: 99%

Increased Rate of Phenocopies in All Age Groups in BRCA1/BRCA2 Mutation Kindred, but Increased Prospective Breast Cancer Risk Is Confined to BRCA2 Mutation Carriers

Evans

Ingham

Buchan

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: To establish, if among unaffected noncarrier relatives in a family with an established BRCA1/2 mutation, there is an increased risk of breast cancer.Methods: We identified 49 women with breast cancer who were first-degree relatives of a pathogenic mutation carrier among 807 BRCA1/2 families but who tested negative for the specific mutation. A prospective analysis of breast cancer from date of family ascertainment was performed for first-degree relatives of proven BRCA1/2 mutation carriers and compared with population-expected incidence rates.Results: Women who prospectively test negative for BRCA1/2 mutations showed excess risk of breast cancer to be confined to BRCA2 noncarriers with an observed:expected (O/E) ratio of 4.57 [95% confidence interval (CI) 2.50-7.67; P < 0.0001; O/E in BRCA1 noncarriers, 1.77]; this dropped to 2.01 for BRCA2 [relative risk (RR), 1.99; 95% CI, 0.54-5.10] from date of predictive test. Genotyping of 18 breast cancer susceptibility singlenucleotide polymorphisms (SNP) defined an RR of 1.31 for BRCA2 breast cancer phenocopies with a breast cancer diagnosis at age less than 60 years.Conclusion: Noncarriers remain at risk in the prospective follow-up of women who tested negative for BRCA1/2. Women testing negative in BRCA2 families may have increased risk of breast cancer compared with population levels, particularly with strong breast cancer history in close relatives. Any increased risk in BRCA1 families is likely to be insufficient to recommend additional interventions.Impact: Our work can help with counseling women from BRCA1/2 families who have tested negative, and could impact on how individual breast cancer risk is related back to these women. Cancer Epidemiol Biomarkers Prev; 22(12); 2269-76. Ó2013 AACR.

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Breast cancer susceptibility variants alter risks in familial disease

Cited by 36 publications

References 25 publications

Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

Increased risk of breast cancer in individuals carrying the TNRC9 rs3803662 C>T polymorphism: a meta-analysis of case-control studies

Increased Rate of Phenocopies in All Age Groups in BRCA1/BRCA2 Mutation Kindred, but Increased Prospective Breast Cancer Risk Is Confined to BRCA2 Mutation Carriers

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