Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals

Frank, Thomas; Deffenbaugh, Amie M.; Reid, Julia; Hulick, Mark; Ward, Benjamin D.; Lingenfelter, Beth; Gumpper, Kathi L.; Scholl, Thomas; Tavtigian, Sean V.; Pruss, Dmitry; Critchfield, Gregory C.

doi:10.1200/jco.20.6.1480

Cited by 634 publications

(528 citation statements)

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“…These observations are in agreement with large studies on ovarian cancer patients (Risch et al, 2001;Frank et al, 2002). It has repeatedly been shown that only a small percentage of BRCA-positive ovarian cancer cases occur at ages o40 years (Boyd et al, 2000;Liede et al, 2002).…”

Section: Discussionsupporting

confidence: 91%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5 þ 3A4G, 2478 -2479insG, E1221X and BRCA2 IVS6 þ 1G4A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (Po0.001), and the presence of a relative with ovarian cancer (Po0.0001) or multiple primary breast cancers (P ¼ 0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P ¼ 0.002). Mutations in the 5 0 -end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast -ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families. Since the mapping and the cloning of two genes that confer susceptibility to both breast and ovarian cancer, BRCA1 and BRCA2 (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996), it became possible to offer genetic testing to families with a predisposition for breast and/or ovarian cancer. Consequently, individuals at risk can now be identified as candidates for surveillance programmes. A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1/2 mutations is well recognised. In some populations or ethnic groups, founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies.To date, no comprehensive studies in the Belgian population have been published. Only data from small series are available (Claes et al, 1999a, b) or from studies in which the analysis was restricted to a few BRCA1/2 exons or to BRCA1 only Sibille-Hoang et al, 1998;Goelen et al, 1999). We performed mutation screening of the complete coding region of BRCA1 and BRCA2 in 349 unrelated Belgian families referred to our family cancer clinic and report here the nature and distribution of the mutations identified. We found phenotypic differences between families in whom a disease-causing mutation was identified vs BRCA1/2 muta...

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Section: Discussionsupporting

confidence: 91%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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“…All samples were analyzed for BRCA1 and BRCA2 through full gene sequencing and rearrangement testing per published protocol [42] through Myriad Genetics Laboratories Inc. This analysis identifies gene mutations in all of the known protein coding sequences and additional adjacent areas in the genes and detects approximately 90-95% of mutations in BRCA1 and BRCA2.…”

Section: Brca1 and Brca2 Analysismentioning

confidence: 99%

Improved survival in BRCA2 carriers with ovarian cancer

et al. 2006

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Objectives-The objective of this study was to investigate survival of ovarian cancer patients with BRCA1 and BRCA2 mutations compared to those without mutations in a population-based sample of incident epithelial ovarian cancer cases. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript the two analyses were similar, thus data involving the 209 invasive epithelial cancer cases are presented, as this was judged to be more clinically relevant. NIH Public AccessResults-In the multivariate analysis, BRCA status and stage were statistically significant, and were adjusted for in the survival analysis model. The Kaplan-Meier method estimated expected survival at 4 years of 83% of BRCA2 carriers compared to 37% of BRCA1 carriers and 12% of non-carriers. There was a statistically significant difference between BRCA2 carriers and noncarriers (p = 0.013). No statistically significant survival differences were seen for BRCA1 carriers when compared with either BRCA2 carriers or non-carriers.Conclusion-These data suggest that BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers. The etiology of this possible survival advantage is currently unknown. Larger studies are needed to confirm these results and to clarify their etiology and clinical significance.

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“…To obtain optimal ascertainment, many risk assessment models and prior probability models have been developed and evaluated (de la Hoya et al, 2003;Domchek et al, 2003). Four such models, the Claus, Gilpin, Frank and Evans model (Claus et al, 1998;Gilpin et al, 2000;Frank et al, 2002;Evans et al, 2004) are empirically derived scoring systems, easy to apply in daily practice with the use of a pencil and a paper and easy to understand for both counsellor and patient.With the Claus tables the probability of developing breast cancer can be determined, but not the likelihood of detecting a BRCA mutation (as in prior probability models). These tables are based on series of unselected women with breast cancer.…”

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confidence: 99%

Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ‘easy to apply’ probability models

et al. 2006

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To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of the Frank (Myriad), Gilpin (family history assessment tool) and Evans (Manchester) model was analysed, to select 49 BRCA mutation-positive families. For various cutoff levels and combinations, the sensitivity and specificity were calculated and compared. The best combinations were subsequently validated in additional sets of families. Comparable sensitivity and specificity were obtained with the Gilpin and Evans models. They appeared to be complementary to the Frank model. To obtain an optimal sensitivity, five 'additional criteria' were introduced that are specific for the selection of small or uninformative families. The optimal selection is made by the combination 'Frank X16% or Evans2 X12 or one of five additional criteria'. The efficiency of the selection of families for mutation testing of BRCA1 and BRCA2 can be optimised by using a combination of available easy to apply risk assessment models. British Journal of Cancer (2006) Identification of families at high risk of hereditary breast and/or ovarian cancer contributes to the prevention and early detection of breast and ovarian malignancies. Therefore, genetic testing is offered to women with an increased risk of hereditary breast or ovarian cancer based on familial clustering of breast and/or ovarian cancer, particularly in case of early onset or if breast cancer occurs in a male. Selection criteria to test for BRCA mutations vary. Because BRCA testing is laborious and expensive, as well as associated with medical, psychological and social consequences for the patient, careful patient selection is required before testing. To obtain optimal ascertainment, many risk assessment models and prior probability models have been developed and evaluated (de la Hoya et al, 2003;Domchek et al, 2003). Four such models, the Claus, Gilpin, Frank and Evans model (Claus et al, 1998;Gilpin et al, 2000;Frank et al, 2002;Evans et al, 2004) are empirically derived scoring systems, easy to apply in daily practice with the use of a pencil and a paper and easy to understand for both counsellor and patient.With the Claus tables the probability of developing breast cancer can be determined, but not the likelihood of detecting a BRCA mutation (as in prior probability models). These tables are based on series of unselected women with breast cancer. As this model does not account for breast cancer in more than two family members, the presence of ovarian cancer, male breast cancer or bilateral breast cancer, it underestimates the cancer risk in many families and cannot be used solely as a prediction model in the clinic.The Frank model, developed by Myriad Genetics, is an empirical model correlating the prevalence of BRCA mutations with personal and family history of breast and ovarian can...

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Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals

Abstract: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.

Cited by 634 publications

References 28 publications

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

Improved survival in BRCA2 carriers with ovarian cancer

Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ‘easy to apply’ probability models

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