One In Four Indian Breast Cancer Patients Carries Inherited Genetic Variant Beyond BRCA Genes: IIT Madras Study
The findings were published in BMC Cancer, a high-impact specialist journal in oncology.
Published : March 2, 2026 at 4:25 PM IST
Chennai: The Indian Institute of Technology Madras (IIT Madras), in collaboration with Karkinos Healthcare Pvt. Ltd., has conducted one of the largest breast cancer genomics studies undertaken in India. The study, which also involved Kumaran Hospital and Chennai Breast Centre, found that nearly one in four Indian breast cancer patients carries an inherited genetic variant linked to cancer risk. The majority of these variants occur outside the well-known BRCA1 and BRCA2 genes.
The findings were published in BMC Cancer, a high-impact specialist journal in oncology. The research paper was co-authored by John Peter, Jayalakshmi Jothi, Avrajit Chakraborty and Prof. S. Mahalingam from the National Cancer Tissue Biobank, Department of Biotechnology, IIT Madras; Bani Jolly, Rajdeep Raha, Vinod Scaria and Sridhar Sivasubbu from Karkinos Healthcare Pvt. Ltd.; Swaminathan Ganapathi Raman from the Department of Oncology, Kumaran Hospital, Chennai; and Selvi Radhakrishnan from Chennai Breast Centre.
The study analysed germline DNA from 479 unselected breast cancer patients, with samples sourced from the National Cancer Tissue Biobank at IIT Madras. This is one of the most comprehensive hereditary breast cancer datasets generated in India so far. The dataset is now part of the Bharat Cancer Genome Atlas, which is the country's first and largest open-source cancer genome data resource.
Talking about the key findings, Prof. S. Mahalingam, Head of the National Cancer Tissue Biobank at IIT Madras and lead author of the study, said, "Our findings have direct implications for clinical practice, public health policy and national cancer guidelines. With approximately one in four Indian breast cancer patients carrying an inherited pathogenic variant and most of these variants lying outside BRCA1/2 the study makes a compelling case for shifting from BRCA-only testing to broader multi-gene panel or exome-based germline testing in India."
"The data also reinforce the need for India and South Asia-specific variant databases and interpretation frameworks to avoid misclassification and ensure accurate risk assessment in diverse populations."
Dr John Peter, the first author of the study, said, "Beyond cancer risk, the study uncovered important secondary health risks. More than 21 per cent of patients carried actionable variants in non-cancer genes associated with conditions like Marfan syndrome, malignant hyperthermia susceptibility, inherited cardiac arrhythmias and familial hypercholesterolaemia. About 8 per cent were carriers of recessive metabolic and genetic disorders, including biotinidase deficiency and Wilson disease."
Dr. Bani Jolly added, "The study also highlights the importance of pharmacogenomics in chemotherapy safety. Clinically significant DPYD variants known to cause severe toxicity with fluoropyrimidine drugs such as 5-FU and capecitabine were observed at measurable frequencies in this Indian cohort. The researchers detected the c.1679T>G (HapB3) variant in 3.13 per cent and the c.1905+1G>A variant in 1.67 per cent of patients, supporting strong consideration for routine DPYD genotyping prior to treatment initiation."
What is the study
The research team examined 97 cancer susceptibility genes, including BRCA1, BRCA2, and 15 genes involved in the homologous recombination repair pathway. Variants were classified using internationally accepted ACMG/AMP guidelines.
In addition, the researchers assessed pharmacogenomic markers affecting chemotherapy safety, screened for actionable secondary findings in non-cancer genes, and compared variant frequencies with global populations using the gnomAD database to identify Indian-and South Asian-enriched variants.
A special focus was placed on RECQL, an emerging breast cancer gene known to exhibit population-specific patterns. The study found that 24.6 per cent of patients carried at least one pathogenic or likely pathogenic variant. Only 8.35 per cent had BRCA1 or BRCA2 variants, while a significantly larger proportion, 11.9 per cent, had inherited pathogenic variants in genes belonging to the homologous recombination repair pathway.
Overall, 67 per cent of all positive findings occurred in non-BRCA genes, including MLH1, NF1, TP53 and RB1, indicating that the inherited landscape of breast cancer risk in India is far more complex than previously understood.
The researchers also identified multiple ancestry-specific pathogenic variants that were either absent or extremely rare in global datasets. These included an India-enriched BRCA1 variant, c.68_69delAG, and potential India-specific variants in the RECQL gene. Several RECQL variants commonly reported in studies from Quebec, Poland and China were not observed in the Indian cohort, which showed regional and population-driven differences in genetic risk patterns.
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