Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 … families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Authors: K. Kast, K. Rhiem, B. Wappenschmidt, E. Hahnen, J. Hauke, B. Bluemcke, V. Zarghooni, N. Herold, N. Ditsch, M. Kiechle, M. Braun, C. Fischer, N. Dikow, S. Schott, N. Rahner, D. Niederacher, T. Fehm, A. Gehrig, C. Mueller-Reible, N. Arnold, N. Maass, G. Borck, N. de Gregorio, C. Scholz, B. Auber, R. Varon-Manteeva, D. Speiser, J. Horvath, N. Lichey, P. Wimberger, S. Stark, U. Faust, B. H. Weber, G. Emons, S. Zachariae, A. Meindl, R. K. Schmutzler, C. Engel

Date Published: 2nd Mar 2016

Publication Type: Journal article

Human Diseases: breast cancer, ovarian cancer

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. … In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Authors: K. Kast, R. K. Schmutzler, K. Rhiem, M. Kiechle, C. Fischer, D. Niederacher, N. Arnold, T. Grimm, D. Speiser, B. Schlegelberger, D. Varga, J. Horvath, M. Beer, S. Briest, A. Meindl, C. Engel

Date Published: 15th Nov 2014

Publication Type: Not specified

Human Diseases: breast cancer, ovarian cancer

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