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Optimal Selection of Individuals for BRCA Mutation Testing

Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital Manchester, Manchester, United Kingdom

Diana Eccles

Wessex Clinical Genetics Service, Princess Anne Hospital, Coxford Road, Southampton, United Kingdom

To the Editor:

We are writing with regard to the recent article published in the Journal of Clinical Oncology by James et al.¹ The authors compared a number of models and scoring systems in the ability to prioritise families for BRCA1 and BRCA2 mutation testing. In assessing 246 families in which 37 pathogenic mutations were found, they concluded that the highest accuracy was achieved with the Bayesian probabilistic model: BRCAPRO. In addition, they must be congratulated on adapting and improving the model by incorporating tumor characteristics. Their comparisons with the newly developed Manchester scoring system^2,3 are, however problematic. In Table 1, they give limitations of each model and they clearly state that the Manchester Score is not suitable for Ashkenazi Jewish families. Nonetheless, all their statistical analyses, receiver operating characteristic curves, pairwise comparisons, and tables have been derived including 37 Ashkenazi Jewish samples. While they did recalculate the scores excluding the Jewish samples, these data are sequestered in the text and then promptly dismissed. The data on the sensitivity and specificity at the 10% detection level for each gene was also not included. James et al should either have excluded the Jewish samples totally or shown separate analyses with the Manchester Scores not included in the total sample set as was presented in another recent article.⁴ Although they¹ did not provide the data for the other models excluding the Jewish samples, the reason for a lack of statistical difference is probably due to the closeness of the scores rather than reduction in sample size. The overall sensitivity and specificity of the Manchester Score at the 10% level excluding the Jewish samples was 81% and 58%, which is little different to the unmodified BRCAPRO specificity and sensitivity of 79% and 61% for all samples. Indeed, the sensitivity of the Manchester score was better than other models including BRCAPRO in the North American analysis,⁴ though this was compromised by poorer specificity. Therefore, the conclusion line in the abstract by James et al, that formal probabilistic models provide significantly greater accuracy in selection of families than scoring methods, is inaccurate. It is clear that the ideal method of case selection is not yet available and that better methods need to be developed if economically sensible, carefully targeted application of genetic testing is to become widely available. The utility of an article rather than computer software based model in selecting cases, is in its rapid accessibility to anyone in any setting and such a method is useful as a method for selecting cases at a first pass for further consideration of whether genetic testing is indicated. Marginal differences in accuracy are not really relevant.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. James PA, Doherty R, Harris M, et al: Optimal selection of individuals for BRCA mutation testing: A comparison of available methods. J Clin Oncol 24:707-715, 2006[Abstract/Free Full Text]

2. Evans DGR, Eccles DM, Rahman N, et al: A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41:474-480, 2004[Abstract/Free Full Text]

3. Evans DGR, Lalloo F, Wallace A, et al: An update on the Manchester Scoring System for BRCA1 and BRCA2 testing. J Med Genet 42:e39, 2005[Free Full Text]

4. Barcenas CH, Hosain M, Arun B, et al: Assessing BRCA carrier probabilities in extended families. J Clin Oncol 24:354-360, 2006[Abstract/Free Full Text]

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