|LETTER TO EDITOR
|Year : 2020 | Volume
| Issue : 2 | Page : 379-380
Authors' reply to Agrawal et al., Laishram, Rathore et al., and Verma et al.
Pratiksha Chheda, Sushant Vinarkar, Kirti Chadha
Department of Integrated Oncopathology, Metropolis Healthcare Ltd., Mumbai, Maharashtra, India
|Date of Submission||17-Apr-2020|
|Date of Decision||17-Apr-2020|
|Date of Acceptance||25-May-2020|
|Date of Web Publication||19-Jun-2020|
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Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chheda P, Vinarkar S, Chadha K. Authors' reply to Agrawal et al., Laishram, Rathore et al., and Verma et al. Cancer Res Stat Treat 2020;3:379-80
We thank Agrawal et al., Laishram, Rathore et al., and Verma et al. for their thoughtful letters regarding our original article and the accompanying editorial.,
We appreciate the critical comments by Agrawal et al. that large genomic rearrangements (LGRs) such as large deletions/insertions/rearrangements, which on an average account for 15% of the mutations, may be missed by sequencing tests, and therefore, methods such as multiplex ligation-dependent probe amplification (MLPA) are needed. As highlighted by Kim et al., in the Korean population, LGRs were seen in 7% of the Sanger-negative, high-risk patients and accounted for 13% of all BRCA1 mutations and 2% of all the mutations reported in these patients. Therefore, if BRCA1/2 mutations are not detected by sequencing technique, additional testing by methods such as MLPA needs to be performed. Moreover, it would be worthwhile to study the frequency of LGRs in the Indian hereditary breast–ovarian cancer (HBOC) cohorts by MLPA. Dr. Laishram has raised a concern about the geographic locations of the subject not being mentioned. The study was conducted in a global reference laboratory which receives samples from different parts of India. Therefore, we agree with Dr. Laishram that the prevalence may vary across the country, and hence, more studies pertaining to specific regional cohorts are warranted. Furthermore, next-generation sequencing (NGS) being a high-throughput technology is at present the superior method for the identification of BRCA variants. Nevertheless, Sanger sequencing is ideal for the confirmation of variants detected by NGS.
Rathore et al. have very well highlighted that molecular genetic testing ideally should be performed initially on the “best test candidate” as opposed to a family member who may not have a personal history of cancer. If the “best test candidate” is not available, molecular testing may be performed on another individual, without a history of cancer. However, it is necessary to understand that failure to detect a pathogenic variant does not eliminate the possibility of a BRCA1/2 pathogenic variant being present in the family. We agree that in case of a very high suspicion of hereditary cancers in the family, a multigene panel including the BRCA1/2 genes is an apt recommendation.
In response to the questions raised by Verma et al. regarding the underrepresentation of the triple-negative breast cancer (TNBC) cohort aged <60 years and overrepresentation of the ovarian cancer cohort, we would explain that our cohort comprised referral cases and the inclusion criteria were as per the National Comprehensive Cancer Network Guidelines. Furthermore, there is a general consensus in the literature that TNBC presents at a younger age, thus explaining the fewer number of TNBC cases with age >60 years. We agree with Verma et al.'s suggestion that sharing of the variant data in public databases needs to be encouraged. This will help in creating a database of variants relevant to different regions of India and also in classifying the variants of unknown clinical significance.
More similar studies are needed, with the documentation of the mutation spectrum of the BRCA gene, thus helping in better understanding the spectrum of BRCA mutations in HBOC in the Indian population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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