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The BRCA mutation spectrum among breast and ovarian cancers in India: highlighting the need to screen BRCA1 185delAG among South Indians

European Journal of Human Genetics (2024)Cite this article

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Abstract

Mutations in BRCA1 and BRCA2 significantly elevate the risk of developing breast and ovarian cancer. Limited data exists regarding the prevalence of BRCA mutations, and optimal, cost-effective testing strategies in developing countries like India. This study aimed to evaluate the utility of a Next Generation Sequencing (NGS) panel for BRCA1/2 mutation testing among women diagnosed with, or at risk of developing hereditary breast and ovarian cancers. We also aimed to identify population specific BRCA1/2 mutation hotspots, to enable the development of more affordable testing strategies. We identified 921 patients with breast and ovarian cancer who underwent mutation testing. The target enrichment was followed by targeted NGS in 772 patients and an allele-specific PCR (ASPCR) based genotyping for BRCA1:c.68_69delAG (or 185delAG), was carried out in 149 patients. We identified 188 (20.4%) patients with BRCA1/2 variants: 118 (62.8%) with pathogenic/likely pathogenic and 70 (37.2%) with VUS. The 185delAG was identified as a recurrent mutation in the Southern Indian population, accounting for 24.6% of the pathogenic variants. In addition, a family history of breast, ovary, pancreas, or prostate (BOPP) cancer was found to be associated with an increased risk of identifying a deleterious BRCA1/2 variant [OR = 2.11 (95% CI 1.45–3.07) p ≤ 0.001]. These results suggest that Targeted NGS is a sensitive and specific strategy for BRCA testing. For Southern Indian patients, a two-tiered approach can be considered: Initial screening with ASPCR for BRCA1 185delAG followed by NGS for those testing negative. Expanding the gene panel and identifying other population-specific mutation hot spots is a promising area with potential for improvements in testing and treatment strategies.

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Fig. 1: Gel electrophoresis images of the exons of BRCA1 and BRCA2 genes.
Fig. 2: Gel electrophoresis image of ASPCR and validation of the hotspot 185delAG using sanger sequencing.
Fig. 3
Fig. 4

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Data availability

The datasets that have been generated and/or analyzed in the course of the current study are accessible through the corresponding author and can be obtained upon request.

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Acknowledgements

We would like to thank all our patients and their families for their consent and participation in the study. We acknowledge Mrs. Manika Varshini and Ms. Judith Evangeline for their involvement in the initial stages of the study.

Funding

There was no specific funding for this manuscript.

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Author notes

  1. These authors contributed equally: Ashish Singh, Pratibha Yadav.

  2. These authors jointly supervised this work: Anjana Joel, Divya Bala Thumaty.

Authors and Affiliations

  1. Department of Medical Oncology, Christian Medical College (CMC), Vellore, India

    Ajoy Oommen John, Ashish Singh, Anjana Joel, Divya Bala Thumaty, K. Fibi Ninan, Josh Thomas Georgy & Raju Titus Chacko

  2. Molecular Endocrinology Laboratory, Department of Endocrinology, Diabetes and Metabolism, CMC, Vellore, India

    Pratibha Yadav, Deny Varghese, R. Parthiban, Lavanya Ravichandran, Jabasteen Johnson, Nihal Thomas & Aaron Chapla

  3. Department of Endocrine Surgery, CMC, Vellore, India

    Anish Jacob Cherian, Shawn Thomas, Deepak Abraham & M. J. Paul

  4. Department of Gynaecologic Oncology, CMC, Vellore, India

    Anitha Thomas, Vinotha Thomas & Abraham Peedicayil

  5. Department of Biostatistics, CMC, Vellore, India

    Bijesh Yadav

  6. Department of Radiation Oncology, CMC, Vellore, India

    S. Patricia & B. Selvamani

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Contributions

Study conception and design: Dr. Aaron Chapla and Dr. Ashish Singh. NGS and ASPCR design and standardization: Dr. Aaron Chapla, Mrs. Deny Varghese, Mr. Parthiban R. Material preparation, data collection, analysis: Dr. Ajoy Oommen John, Dr. Ashish Singh, Dr. Anjana Joel, Ms. Pratibha Yadav, Dr. Divya Bala Thumaty, Dr. Fibi Ninan K, Dr. Josh Thomas Georgy, Dr. Anish Jacob Cherian, Dr. Shawn Thomas, Dr. Anitha Thomas, Dr. Vinotha Thomas, Dr. Abraham Peedicayil, Ms. Lavanya Ravichandran, Mr. Jabasteen Johnson, Dr. Bijesh Yadav, Dr. Patricia S, Dr. Selvamani B, Dr. Deepak Abraham, Dr. MJ Paul, Dr. Raju Titus Chacko, Dr. Nihal Thomas, Dr. Ashish Singh, Dr. Aaron Chapla. First draft of the manuscript was written by Dr. Ajoy Oommen John, Dr. Aaron Chapla, Dr. Ashish Singh and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Aaron Chapla.

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This study was approved by the institutional review board IRB no 13205 (retro) dated 22.07.2020.

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Informed consent was obtained from all individual participants included in the study.

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John, A.O., Singh, A., Yadav, P. et al. The BRCA mutation spectrum among breast and ovarian cancers in India: highlighting the need to screen BRCA1 185delAG among South Indians. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01596-w

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