Risks of cancer due to a single BRCA1 mutation in an extended Utah kindred

Vogl, Florian D.; Badzioch, Mike D.; Steele, Linda; Neuhausen, Susan L.; Goldgar, David E.

doi:10.1007/s10689-006-9106-8

Cited by 4 publications

(3 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eleven were Kaplan-Meier analyses (including three analyses of incident cases and two analyses with bootstrapping), 6,14,19,21,28,37,40,44,[50][51][52][53] four were frailty models, and four were modified segregation analyses. 24,25,27,29,41,54 Kaplan-Meier analysis.…”

Section: Methods To Estimate the Risk Of Breast Cancer In Brca1/2 Carmentioning

confidence: 99%

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers

Vos

Hsu

Brohet

et al. 2015

JCO

View full text Add to dashboard Cite

Purpose Recommendations for treating patients who carry a BRCA1/2 gene are mainly based on cumulative lifetime risks (CLTRs) of breast cancer determined from retrospective cohorts. These risks vary widely (27% to 88%), and it is important to understand why. We analyzed the effects of methods of risk estimation and bias correction and of population factors on CLTRs in this retrospective clinical cohort of BRCA1/2 carriers. Patients and Methods The following methods to estimate the breast cancer risk of BRCA1/2 carriers were identified from the literature: Kaplan-Meier, frailty, and modified segregation analyses with bias correction consisting of including or excluding index patients combined with including or excluding first-degree relatives (FDRs) or different conditional likelihoods. These were applied to clinical data of BRCA1/2 families derived from our family cancer clinic for whom a simulation was also performed to evaluate the methods. CLTRs and 95% CIs were estimated and compared with the reference CLTRs. Results CLTRs ranged from 35% to 83% for BRCA1 and 41% to 86% for BRCA2 carriers at age 70 years width of 95% CIs: 10% to 35% and 13% to 46%, respectively). Relative bias varied from −38% to +16%. Bias correction with inclusion of index patients and untested FDRs gave the smallest bias: +2% (SD, 2%) in BRCA1 and +0.9% (SD, 3.6%) in BRCA2. Conclusion Much of the variation in breast cancer CLTRs in retrospective clinical BRCA1/2 cohorts is due to the bias-correction method, whereas a smaller part is due to population differences. Kaplan-Meier analyses with bias correction that includes index patients and a proportion of untested FDRs provide suitable CLTRs for carriers counseled in the clinic.

show abstract

Section: Methods To Estimate the Risk Of Breast Cancer In Brca1/2 Carmentioning

confidence: 99%

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers

Vos

Hsu

Brohet

et al. 2015

JCO

View full text Add to dashboard Cite

show abstract

“…The risk estimates that are associated with pathogenic mutations in the BRCA1 and BRCA2 genes have been found to vary substantially among studies (Antoniou et al ., ; Begg et al ., ; Brohet et al ., ; Milne et al ., ; Simchoni et al ., ). There is also variability in age at diagnosis and type of cancer in the index case (Antoniou et al ., ), even among women who carry the same BRCA gene mutation (Thorlacius et al ., ) and among women in the same family (Vogl et al ., ). Such evidence suggests that genetic or other factors that cluster in families may modify the cancer risks that are conferred by BRCA1 and BRCA2 mutations.…”

Section: Introductionmentioning

confidence: 97%

Analysis of Multivariate Failure Times in the Presence of Selection Bias with Application to Breast Cancer

Leclerc

Antoniou

Simard

et al. 2014

Journal of the Royal Statistical Society Series C: Applied Statistics

View full text Add to dashboard Cite

Identifying loci that modify the risk of cancer for mutation carriers is an important topic in oncogenetics. Within this research area, we are concerned with the analysis of the association between a genetic variant (single-nucleotide polymorphism rs13281615) and breast cancer among women with a pathogenic mutation in the BRCA2 gene. As this mutation is rare, data were collected retrospectively according to a case-study design through genetic screening programmes. This involves a selection bias and an intrafamilial correlation, which complicates the statistical analysis. We derive a Cramer-von Mises-type statistic to test the equality of genotype-specific survival functions when the proportional hazards model does not hold. A Clayton copula is specified to model the residual phenotype familial dependence and an innovative semiparametric bootstrap procedure is proposed to approximate the distribution of the test statistic under the null hypothesis. The test proposed is applied to data from European and North American mutation carriers and its performance is evaluated by simulations.

show abstract

“…Lifetime risks for breast cancer range from 40–87% and for ovarian cancer from 11–68% (1, 2). In addition to variability in the incidence of breast and ovarian cancers, there is also variability in age at diagnosis and type of cancer in the index case (proband) (1), even among women who carry the same BRCA mutation (3) and among women in the same family (4). These observations suggest that cancer risk in mutation carriers is modified by other genetic and/or environmental factors.…”

Section: Introductionmentioning

confidence: 99%

A Nonsynonymous Polymorphism inIRS1Modifies Risk of Developing Breast and Ovarian Cancers inBRCA1and Ovarian Cancer inBRCA2Mutation Carriers

Ding¹,

McGuffog²,

Healey³

et al. 2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

View full text Add to dashboard Cite

Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

show abstract

Risks of cancer due to a single BRCA1 mutation in an extended Utah kindred

Abstract: Estimating the penetrance of a specific mutation using different approaches, we found that both the choice of study population and statistical method affect the magnitude of the estimates.

Cited by 4 publications

References 13 publications

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers

Analysis of Multivariate Failure Times in the Presence of Selection Bias with Application to Breast Cancer

A Nonsynonymous Polymorphism inIRS1Modifies Risk of Developing Breast and Ovarian Cancers inBRCA1and Ovarian Cancer inBRCA2Mutation Carriers

Contact Info

Product

Resources

About