Assessing <i>BRCA</i> Carrier Probabilities in Extended Families

Barcenas, Carlos H.; Hosain, G. M. Monawar; Arun, Banu K.; Zong, Jihong; Zhou, Xiangzhi; Chen, Jianfang; Cortada, Jill M.; Mills, Gordon B.; Tomlinson, Gail E.; Miller, Alexander; Strong, Louise C.; Amos, Christopher I.

doi:10.1200/jco.2005.02.2368

Cited by 91 publications

(78 citation statements)

References 25 publications

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“…The program allows for families of any size or structure; pedigrees built online are restricted to first-and second-degree relatives but uploaded files can be of arbitrary complexity. It has been shown that relatives more distant than second degree can provide important information for risk models (Antoniou et al, 2005;Barcenas et al, 2006). The BOADICEA returns both predicted probabilities of carrying a BRCA1 or a BRCA2 mutation, and risks (by the age of up to 80 years) of developing breast or ovarian cancer for unaffected individuals, or the risk of contralateral breast cancer or ovarian cancer for those who have already developed a first breast cancer.…”

Section: Discussionmentioning

confidence: 99%

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

et al. 2008

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Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920 -1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program

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Section: Discussionmentioning

confidence: 99%

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

et al. 2008

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“…Although the performance of some of these models has been previously examined, it is perhaps telling that no single model has been universally adopted. Previous model validation studies have considered only a subset of the available models, have not compared the results with germline testing, and have not considered the barriers to the use of models in clinical practice (Berry et al, 2002;Euhus et al, 2002;de la Hoya et al, 2003;Marroni et al, 2004;James et al, 2006;Barcenas et al, 2006). This study sought to compare the ability of four models (BRCAPRO, Manchester, Penn and the Myriad-Frank) to determine the likelihood of finding a BRCA gene mutation in at-risk individuals using a large group of patients who had undergone germline testing.…”

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confidence: 99%

Evaluation of models to predict BRCA germline mutations

et al. 2006

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The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66 -2.67) for Penn, 1.74 (95% CI 1.48 -2.04) for Myriad, 1.35 (95% CI 1.19 -1.53) for Manchester and 1.68 (95% CI 1.39 -2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.

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“…Several other groups have been evaluating risk prediction model performance [19][20][21][22][23][24]. James et al [20] studied 257 probands from a cancer family clinic in Melbourne, Australia (27% with mutations) and compared performance of the Myriad, Couch, BRCAPRO, FHAT [25] and MANCHESTER [26] approaches.…”

Section: Discussionmentioning

confidence: 99%

“…They found, as we did, that BRCAPRO over-predicted carriers with high predicted probabilities. Barcenas et al [22] studied 472 probands (21% AJ) and compared BRCAPRO, BOADICEA, Myriad II, Manchester and Couch models. The conclusion was BOADICEA performed better than the other models for AJ families, while overall, BRCAPRO, BOADICEA, and Myriad II performed similarly with Myriad II being the easiest of these to use.…”

Section: Discussionmentioning

confidence: 99%

Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models

Lindor

Apicella

et al. 2007

Familial Cancer

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Context-Models have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is unclear.Objective-To compare the performance characteristics of four BRCA1/BRCA2 gene mutation prediction models: LAMBDA, based on a checklist and scores developed from data on Ashkenazi Jewish (AJ) women; BRCAPRO, a Bayesian computer program; modified Couch tables based on regression analyses; and Myriad II tables collated by Myriad Genetics Laboratories.Correspondence to: Noralane M. Lindor, nlindor@mayo.edu. NIH Public Access Author ManuscriptFam Cancer. Author manuscript; available in PMC 2010 September 3. Design and setting-Family cancer history data were analyzed from 200 probands from the Mayo Clinic Familial Cancer Program, in a multispecialty tertiary care group practice. All probands had clinical testing for BRCA1 and BRCA2 mutations conducted in a single laboratory.Main outcomes measures-For each model, performance was assessed by the area under the receiver operator characteristic curve (ROC) and by tests of accuracy and dispersion. Cases "missed" by one or more models (model predicted less than 10% probability of mutation when a mutation was actually found) were compared across models.Results-All models gave similar areas under the ROC curve of 0.71 to 0.76. All models except LAMBDA substantially under-predicted the numbers of carriers. All models were too dispersed.Conclusions-In terms of ranking, all prediction models performed reasonably well with similar performance characteristics. Model predictions were widely discrepant for some families. Review of cancer family histories by an experienced clinician continues to be vital to ensure that critical elements are not missed and that the most appropriate risk prediction figures are provided.

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Assessing BRCA Carrier Probabilities in Extended Families

Abstract: The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Cited by 91 publications

References 25 publications

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Evaluation of models to predict BRCA germline mutations

Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models

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