We thank the readers of our manuscript for the careful reading and the constructive
criticisms that they provide. In response to their comments we offer the following
clarifications:
- 1.The recruitment method of the general population in our study.—Since all comers to the medical center were eligible, there is no selection bias as such. This method of recruitment is robust enough and represents the general population with the obvious limitations. There is no a priori reason to suspect that cancer free patients who are referred to the outpatient clinic in a large medical center woulddeviate significantly from the general population in the same geographical region. Admittedly, if newborn screening was possible it would be a better choice, but this was not feasible given the current study scope. All recruitment methods of healthy adult individuals in the general population introduce a bias, as these individuals need to be identified, offer participation and are recruited into the study. The extent to which these individuals do or do not represent the general population in MG is speculative at best.
- 2.OC and TP53 mutation.—The conclusions regarding OC cases and TP53 are not the main issue of the OC aspect of the manuscript. The main issue around the genotyping of consecutive OC cases is the rate of the recurring mutation in the BRCA1 gene (5382InsC). As some Brazilian studies reported this mutation occurs at rates that are up to 12% of young cases of breast cancer in Brazil (1). Extrapolating from other populations where a few founder mutations occur (e.g., the Ashkenazi population), it seemed plausible to test the same mutation (as well as other recurring BRCA mutations) in unselected OC cases.
- 3.Regarding population frequency of p.Arg337His.—We appreciate the extent to which the responders took the time to calculate the sample size needed. A more simplistic way of calculating is the following: if the population rate was indeed 0.3%, one would expect to find 2–3 cases in 1000 genotyped individuals and at least 1 in 500. That was clearly not the case. We cannot comment on the 17 cases in 4 families that were identified in MG by the letter writers, as there are no reference and recruitment methods or criteria of recruitment of these 4 families.
- 4.The ethical aspects were not clear.—In the methods section (bottom of the second paragraph) it is clearly stated that the study as a whole was approved by the ethics committee and that each participant gave an informed consent.
- 5.Finally, in the discussion section, the authors state that “(…) it seems that a population-based screening, similar to the one recently advocated for the Ashkenazi Jewish population [6] (and for the South Brazilian population) [7], cannot be advocated for the population of Belo Horizonte in a different region of Brazil”. We believe that the presented study (1) does not have a comparable population to the cited studies [6,7].—We agree that it is not the same populations ethnically and geographically. Yet, the numbers used to assess the rate in the predominant mutations in the Jewish Ashkenazi population in the BRCA1 and BRCA2 genes in the original studies were based on 858–1255 unselected cases (2). If the results of our study (and subsequent expansion studies) would show that the rate of any of the tested mutations in unselected Brazilian population is similar to that of Ashkenazim, we would advocate population screening. We simply said that this recommendation for population screening is not supported by the results of the current study.
- 6.They studied individuals at low risk of carrying mutations in BRCA1, BRCA2 and TP53, while the Ashkenazi Jewish population is known to have high risk of germline mutations in BRCA genes and for this increased mutational frequency (about 2% of the general population of Ashkenazi Jews) it is reasonable to advocate population screening in this specific ethnic group.—That is exactly the point! The Ashkenazi Jews who were genotyped as part of the general population in the original “general population” based studies were all considered average risk for developing cancer, and yet a high rate of carriership of BRCA1 and BRCA2 mutations was noted, even with no personal or family history (2). So where is the criticism?
- 7.Additionally, the authors mention that Ashton-Prolla et al. (1) recommend population screening in southern Brazil for the general population, which is inaccurate since this recommendation was not made in the reference cited.—We apologize for that but the call for sequencing the general population in that part of the country for all newborns for the R337H TP53 mutation was made in another manuscript added below (3).
- 8.Finally, in order to properly estimate the prevalence of mutations at the populational level, people from different ages and regions in the MG population, and with different probabilities of developing or not developing cancer (as occurs in the general population), should be studied. Furthermore, it is necessary to consider estimated frequencies from other studies to calculate the minimum sample size to be evaluated.—See our response to the first comment.
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References
- Prevalence and impact of founder mutations in hereditary breast cancer in Latin America.Genet Mol Biol. 2014; 37: 234-240
- The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.Nat Genet. 1996; 14: 188-190
- Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors.J Clin Oncol. 2013; 31: 2619-2626
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Published online: April 22, 2016
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