Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea

Round 1

Reviewer 1 Report

I appreciated the authors' effort to develop an independent genetic test to achieve easier data availability. Obviously, the method must be improved by means of a long-term prospective study and with an adequate number of samples.

Author Response

Thanks for your thoughtful review. Because this study has a definite limitation due to the characteristic of a retrospective study and I deeply agree with you, your point is described as a limitation in Line 362 of Discussion part. I also added "with more sufficient number of samples" in Line 365 as you concerned.

I would try to perform a well-designed long-term prospective study with more sufficient number of samples to make real world evidence in a near future. To broaden the local gBRCA 1/2 mutation testing, this study needs to be published.

Reviewer 2 Report

Overall this is a nice study showing how a local laboratory performs compared to Myriad.  The findings are not surprising, but it is worth having them available in the literature.  The language and phrasing is reasonable but somewhat awkward in places.  If further edits are made to the paper it would be worth the time to clarify some of the language.

Author Response

Thanks for your thoughtful review.

I corrected the tense for more proper expression in Line 61. I made spacing words between numbers and units "%" in the text and tables. I also added missing units "%" in Table 1 and Table 2. Right before submitting, professional English editing company composed of native Americans edited. I would attach the certificate of editing. If you point out the awkward part, I'll ask the company for correction again.

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

This reviewer reviewed the manuscript entitled “Local laboratory testing of germline BRCA mutations vs. Myriad: A single-institution experience in Korea” by Joohyun Hong et al. This study analyzed the genetic diagnosis for HER2-negative metastatic breast cancer patients with germline BRCA (gBRCA) mutation since the development of PARP1 inhibitors. Myriad Genetics, Inc. (UT, USA)’s companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of gBRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe am-plification (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% the sample, six patients. All discrepancies were generated during interpretation of BRCA 2 gene se-quencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

This reviewer think that this manuscript is interesting on comparing the local laboratory testing between gBRCA mutations vs. Myriad, however, the tested cases are limited. The reviewer also think how and by which data base the authors diagnosed gBRCA mutation in Samsung Medical Center. The information is interesting as local laboratory tests however, the information is limited.

Author Response

Thanks for your thoughtful review.

For more proper expression, I corrected the tense for more proper expression in Line 61. I made spacing words between numbers and units "%" in the text and tables. I also added missing units "%" in Table 1 and Table 2. Right before submitting, professional English editing company composed of native Americans edited. I would attach the certificate of editing. If you point out the awkward part, I'll ask the company for correction again. Please see the attachment.

Because this study has a definite limitation due to the characteristic of a retrospective study and I deeply agree with you, your point is described as a limitation in Line 362 of Discussion part. I also added "with more sufficient number of samples" in Line 365 as you concerned. I would try to perform a well-designed long-term prospective study with more sufficient number of samples to make real world evidence in a near future. To broaden the local gBRCA 1/2 mutation testing, this study needs to be published.

Author Response File: Author Response.pdf

Reviewer 4 Report

The manuscript "Local laboratory testing of germline BRCA mutations vs. Myriad: A single-institution experience in Korea" by Hong et al. compares two genetic tests in order to evaluate discrepancies or concordances. I found the manuscript well written and very clear. It is highly  relevant to the journal. Methods and results are described well; I have some comments about the discussion and conclusions.

The number of cases is quite low; could this affect the comparisons?

74% concordance is not bad, but 22% discordand on VUS classification is quite high. Of course, test standardization needs to be improved; my questions are; what exactly needs to be improved and standardized, protocols? classification rules? both?  does re-sequencing make mistakes? I would add a little more explaination about that.

In conclusion, I think that the manuscript is acceptable wit minor changes

Thanks

 

 

Author Response

Thanks for your thoughtful review.

I corrected the tense for more proper expression in Line 61. I made spacing words between numbers and units "%" in the text and tables. I also added missing units "%" in Table 1 and Table 2. Right before submitting, professional English editing company composed of native Americans edited. I would attach the certificate of editing. If you point out the awkward part, I'll ask the company for correction again. Please see the attachment.

Because this study has a definite limitation due to the characteristic of a retrospective study and I deeply agree with you, your point is described as a limitation in Line 362 of Discussion part. I also added "with more sufficient number of samples" in Line 365 as you concerned. I would try to perform a well-designed long-term prospective study with more sufficient number of samples to make real world evidence in a near future. To broaden the local gBRCA 1/2 mutation testing, this study needs to be published.

As described in Line 335, both need to be improved. (Standards for the genetic testing of BRCA 1/2 genes do not exist, including methods, types of software and analytical tools, criteria for interpreting test results, databases utilized,  categories, types of clinical information referenced, or types of references used for considering population  frequency [25].) While sequencing results of these discrepancies were exactly identical, the interpretations of the identical sequencing were different as described in Line 332. I added similar cases and insisted the necessity of gBRCA mutation testing standardization, including methods, types of software and analytical tools, criteria for interpreting test results, databases utilized, categories, types of clinical information referenced, or types of references used for considering population frequency in the paragraph(Line 347).

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

The authors have responded all the inquiries by this reviewer. This reviewer approved all the comments for the revised version of the manuscript entitled “

 Title Local laboratory testing of germline BRCA mutations vs. Myriad: A single-institution experience in Korea” by Dr Joohyun Hong et al, is ready for publication consideration in editorial office of “Diagnostics”.