Cancer Research, Statistics, and Treatment

: 2020  |  Volume : 3  |  Issue : 2  |  Page : 377--378

All BRCA of a feather don't flock together

Chaturbhuj R Agrawal1, Makarand Randive2, Venkata Pradeep Babu Koyyala1,  
1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Medical Oncology, Dharamshila Cancer Institute and Research Centre, New Delhi, India

Correspondence Address:
Chaturbhuj R Agrawal
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini Sector 5, New Delhi - 110 085

How to cite this article:
Agrawal CR, Randive M, Koyyala VP. All BRCA of a feather don't flock together.Cancer Res Stat Treat 2020;3:377-378

How to cite this URL:
Agrawal CR, Randive M, Koyyala VP. All BRCA of a feather don't flock together. Cancer Res Stat Treat [serial online] 2020 [cited 2022 Jul 1 ];3:377-378
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We have read with great interest the article by Chheda et al.[1] and the accompanying editorial,[2] and we really appreciate this clearly written and thought-provoking article. The way they comprehensively classified the large spectrum of pathogenic-nonpathogenic BRCA mutants is highly appreciable, and we would like to congratulate the authors for this. However, a few points are worth mentioning. To summarize this article, 160 unrelated women were retrospectively analyzed by their screening findings of BRCA 1 and BRCA 2 genetic mutation testing carried out by Sanger sequencing and next-generation sequencing. This study reported that 31.9% of women had a pathogenic variant in the BRCA gene; categorically, BRCA 1 mutation (70.6%) was higher than BRCA 2 (29.4%). The frequency of mutations was more in women with a personal history of breast or ovarian cancer (34.5%) compared to unaffected family members (25%), and a spectrum of 34 different variants was found in 51 cases.[1]

Considering the method used in the present study, we agree that the majority of BRCA 1/2 alterations are single-base changes or deletions/insertions of a small number of nucleotides which are detected by conventional methods that were used in this study. However, large genomic rearrangements such as large deletions/insertions/rearrangements which account for, on an average 15% (4%–28%) of the mutations, may be missed with conventional modes of testing and need methods such as multiplex Ligand-dependent probe amplification.[3] Considering the age frequencies, a previous study on the Indian population by Vaidyanathan et al.[4] highlighted the fact that there were BRCA 2 mutations in the younger population (all positive cases in persons ≤40 years of age), whereas in the present study, 10/15 cases (66%) were present in women over 40 years old again suggesting a heterogeneous patient group and provoking the thought of testing ≥40-year age group also in the future. Considering variants, the existing literature has already shown that the three most common mutations in the BRCA gene are frameshift mutations, and one of the three founder mutations (BRCA 1 c.68_69delAG, c.5266dupC, and BRCA 2 c.5946delT) are found in the majority of cases.[5] Similar to the published literature, this study also found the 18delAG mutation in the majority of cases. However, there are differences as per race and ethnicity. The c.3700_3704del mutation is frequently detected in the Caucasian population along with a relatively low frequency of the other two founder mutations, c.4034delA and c.68_69delAG. In a previous similar study, 24.6% had BRCA1 mutations and 3.28% had BRCA2 mutation, whereas 23.1% of families with breast cancer carried mutations in the BRCA1 and BRCA2 genes. They too reported three novel mutations (295delCA; 4213T→A; 5267T→G) in BRCA 1.[4] Other Indian studies like that by Valarmathi et al.[6] found five novel pathogenic mutations (c.187_188delAG), (c.3672G>T) of BRCA 1 and (c.5227dupT, c.5242dupT, c. 6180dupA) of BRCA 2 while Saxena et al.[7] identified two novel splice variants (331 + 1G >T; 4476 + 2T>C) in BRCA 1. Similarly, Chakraborty et al.[8] found that 24.6% had BRCA 1 mutation and 7.3% had BRCA 2 mutation. In most cases in the current series, BRCA 1 mutation 185delAG (9.33%) and 5382 InsC (6%) mutations were found. Significantly fewer BRCA 2 mutations (6%) were detected in women with a history of ovarian cancer in the family; however, one family had a case of male breast cancer with BRCA 1 mutation.

The picture about the spectrum of germline BRCA mutations in the Indian subcontinent is evolving with very few existing studies. The advent of poly (ADP-ribose) polymerase inhibitor therapy has not only changed the treatment landscape for patients with breast and ovarian cancer but has also extended the spectrum of indications of testing for BRCA gene from screening to therapeutics, thus driving more and more testing and detecting novel mutations in these genes. However, there remains a wide gap of information on Indian women compared to the Western data of the BRCA mutation profile and the behavior of hereditary breast and ovarian cancer according to the mutation justifying the need for more data from the Indian population before we extrapolate therapeutic decisions to our population.[9] This study by Chheda et al.[1] further supports the previous Indian data and provides new insights by finding novel mutations and variants of unknown significance (VUS). Clinical targeted testing (single-site BRCA analysis) of the VUS in other affected and unaffected family members may help in clarifying the clinical significance of this variant. More of such similar studies need to be conducted to unmask the hidden genetic mutations in the BRCA spectrum.

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