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, D. Gareth; Ingham, Sarah; Buchan, Iain; Woodward, Emma R.; Byers, Helen; Howell, Anthony; Newman, William G.; Lalloo, Fiona

doi:10.1158/1055-9965.epi-13-0316-t

Cited by 14 publications

(16 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some authors have demonstrated that women who come from BRCA1/2 positive families who themselves test negative for a BRCA gene mutation develop breast cancer at a higher rate than expected. (49–51) It has been hypothesized that there are inherited genetic modifiers in these families that increase the risk of breast cancer even in the absence of a deleterious BRCA mutation. It stands to reason that the same could be true for ovarian reserve.…”

Section: Discussionmentioning

confidence: 99%

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

Johnson

Sammel

Domchek

et al. 2017

Fertility and Sterility

View full text Add to dashboard Cite

Objective To compare Anti-Mullerian Hormone (AMH) levels in women at high risk for hereditary breast and ovarian cancer compared to healthy, low-risk controls. Design Prospective cohort Setting Ambulatory Patient(s) Reproductive age women with a uterus and both ovaries were analyzed in four groups: BRCA1 carriers, BRCA2 carriers, BRCA negative, and low-risk controls Intervention(s) Self-collected dried blood spot (DBS) Main Outcome Measure(s) AMH levels Result(s) One hundred ninety-five women were included: 55 BRCA1 carriers, 50 BRCA2 carriers, 26 BRCA negative, and 64 low-risk controls. After adjusting for confounders, BRCA2 carriers had AMH levels that were 33% lower than controls (Geometric Mean Ratio(GMR)=0.67, 95% CI 0.47–0.94) and an increased odds of having AMH<1 ng/mL (OR 3.69, 95% CI 1.34–10.19). BRCA1 carriers and BRCA negative women had similar AMH levels to controls. When analysis was restricted to regularly menstruating women younger than 40, BRCA2 carriers continued to demonstrate significantly lower AMH levels and increased likelihood of low AMH. Also, in this restricted group, BRCA negative women demonstrated AMH levels that were 42% lower than controls (GMR=0.58; 95%CI 0.35–0.95). No difference in AMH was observed among BRCA1 carriers. Conclusion(s) We observed significantly lower AMH levels among BRCA2 carriers compared to low-risk controls. These results were stable across all models. BRCA negative women also had lower AMH values, but only in models restricted to young, regularly menstruating women. In contrast to previous analyses, BRCA1 carriers had AMH values that were similar to low-risk controls, but this may be due to differences in the population studied.

show abstract

Section: Discussionmentioning

confidence: 99%

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

Johnson

Sammel

Domchek

et al. 2017

Fertility and Sterility

View full text Add to dashboard Cite

show abstract

“…152 Increased risk was seen especially in BRCA2 families with high incidence of breast cancer (Manchester BRCA2 score of > 10), potentially implicating unlinked genetic modifiers causing this excess. Genotyping of 18 breast cancer susceptibility SNPs defined a RR of 1.31 for BRCA2 breast cancer phenocopies with a breast cancer diagnosis aged < 60 years.…”

Section: Study 3: Phenocopiesmentioning

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

Self Cite

117

126

View full text Add to dashboard Cite

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.

show abstract

“…The identification of path_BRCA1 or path_BRCA2 in an affected BC individual enables access to evidence-based screening for family members, and thus facilitates the implementation of appropriate cancer prevention in these families [ 1 , 5 , 6 ]. However, some women in families with an identified pathogenic variant will develop cancer despite testing negative for the family’s pathogenic variant, often denoted as phenocopies [ 8 ]. In BC kindreds having a demonstrated path_BRCA2 variant, the number of phenocopies is reportedly more frequent than expected by chance [ 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Dominguez‐Valentin

Evans

Nakken

et al. 2018

Hered Cancer Clin Pract

Self Cite

View full text Add to dashboard Cite

BackgroundIn kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families’ path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families’ pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2).MethodsWomen with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay.ResultsWe identified 48 women who were tested negative for their family’s path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X).ConclusionAll women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.Electronic supplementary materialThe online version of this article (10.1186/s13053-018-0086-0) contains supplementary material, which is available to authorized users.

show abstract

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

Cited by 14 publications

References 27 publications

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

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

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Contact Info

Product

Resources

About