Cancer Research, Statistics, and Treatment

: 2020  |  Volume : 3  |  Issue : 2  |  Page : 376--377

Mutations in BRCA1/2 genes: Unexpected higher prevalence in Indian Patients

Amit Verma1, Pramod Kumar Julka1, Jatinder Kaur2,  
1 Molecular Oncology and Cancer Genetics, Max Institute of Cancer Care, New Delhi, India
2 Department of Research and Development, Molecular Quest Healthcare Pvt. Ltd, Gurgaon, Haryana, India

Correspondence Address:
Amit Verma
2nd, 26A, Ring Road, Vikram Vihar, Lajpat Nagar IV, New Delhi, Delhi - 110 024

How to cite this article:
Verma A, Julka PK, Kaur J. Mutations in BRCA1/2 genes: Unexpected higher prevalence in Indian Patients.Cancer Res Stat Treat 2020;3:376-377

How to cite this URL:
Verma A, Julka PK, Kaur J. Mutations in BRCA1/2 genes: Unexpected higher prevalence in Indian Patients. Cancer Res Stat Treat [serial online] 2020 [cited 2022 Jul 1 ];3:376-377
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Full Text

It was very interesting to read the recent article in your current issue by Chedda et al.[1] and the accompanying editorial,[2] contributing to fulfill the unmet need of Indian statistics on the prevalence of BRCA1/ 2 mutations. Breast cancer is the most common cancer in Indian women, with an incidence rate of 25.8 and a mortality of 12.7/100,000 women.[3] In hereditary breast cancer, where cancer prevention strategies lead to reduction in mortality and morbidity, the incidence is not well reported. In the Western literature, up to 5%–10% of breast cancer cases are known to be hereditary and are associated with mutations predominantly in the BRCA1 and BRCA2 genes.[4] The diversity in the Indian population at multiple levels adds to the diverse spectrum of mutations seen in hereditary breast and ovarian cancer (HBOC) as compared to the Western population.

In the previous issue, Chedda et al.[1] in their study of 160 suspected HBOC Indian patients reported high prevalence (31.9%) of pathogenic variants in BRCA1 ( 22.5%) and BRCA2 ( 9.3%) genes. Similarly, Indian studies from Singh et al.[4] and Selvakumar et al.[5] showed a prevalence of 25.5% and 18.3%, respectively. However, BRCA2 mutation prevalence was much lower (<6%) in other Indian studies. These variations can be explained by the referral bias (reference laboratory vs. hospital laboratory). Authors have attempted to reduce this bias by analyzing the patients meeting the National Comprehensive Cancer Network (NCCN) criteria for gene testing; however, the distribution of the patients in this study cohort does not represent the true prevalence of the disease burden, e.g., women with triple-negative breast cancer aged <60 years were under-represented (10%) and women with ovarian cancer were over-represented (27.5%).

A spectrum of 34 different pathogenic variants was identified in BRCA1/ 2 genes, the most common variant being c.68_69delAG (known to be a founder mutation in Ashkenazi Jewish) and c.5074+1G>A. These variants were frequently reported by Singh et al. conducted in a larger cohort of 1010 HBOC Indian patients,[4] which were characterized further with respect to ethnicity. They characterized c.68_69delAG mutation to be associated mainly with Western India and Southern India and c.5074+1G>A mainly with Western India.[4] However, both studies have limitations and larger studies are required to come up with Indian geographical mutation distribution.

Challenges faced in the clinical practice are to differentiate between clinically significant variations and variants of unknown significance (VUS), as they are known to have clinical implications. The frequency of VUS varies (5%–21%) globally depending on the population being analyzed. Chedda et al.[1] reported VUS to be 6.25% compared to 14.7% in the study by Singh et al.[4] and 8% in the study by Selvakumar et al.[5] Reclassifying 3 of 11 VUS as disease-causing variants [1] underlines the importance of meticulously following up the data.[2]

It would be of clinical relevance to know the prevalence of mutations in the genes besides BRCA1/ 2, where patients met the NCCN criteria but were negative on testing. Additional methods including multigene testing and multiplex ligation-dependent probe amplification for the identification of large deletions and duplications in BRCA1/ 2 genes, if carried out, would have yielded a higher mutation prevalence.

Although large-scale studies are limited in India, the results obtained from smaller cohorts emphasize the need to catalog mutations specific to the Indian population. The studies from India are showing relatively higher prevalence of BRCA1/ 2 mutations as compared to the global data, which cannot be ignored. Larger cohort study is warranted to understand the true prevalence and to devise the indigenous testing criteria and protocols for BRCA1/ 2 and other cancer predisposing genes. Sharing of data should be promoted in public domain that will reduce the VUS percentage and help to reclassify into benign versus pathogenic variants.

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Conflicts of interest

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1Chedda P, Pande S, Dama T, Vinarkar S, Chanekar M, Limaye S, et al. Spectrum of germline BRCA mutations in hereditary breast and ovarian cancer syndrome in Indian population: A central reference laboratory experience. Cancer Res Stat Treat 2020;3:32-41.
2Akram Hussain SM. Molecular-based screening and therapeutics of breast and ovarian cancer in low-and middle-income countries. Cancer Res Stat Treat 2020;3:81-4.
3Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol 2017;13:289-95.
4Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: Prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat 2018;170:189-96.
5Selvakumar VP, Garg S, Kaur J, Kadayaprath G, Rohatgi N, Walia M, et al. Genetic testing for hereditary breast and ovarian cancer in Indian population: A single institutional study. J Clin Oncol 2019;37 Suppl 15:e13153.