IIT Madras, Karkinos Healthcare study reveals 1 in 4 Indian breast cancer patients carry inherited genetic risk variants

New Delhi: Indian Institute of Technology Madras (IIT Madras) and Karkinos Healthcare Researchers have conducted one of the largest breast cancer genomics studies undertaken in India.

Their study, which also involved Kumaran Hospital, Chennai, and Chennai Breast Centre, found that one in four Indian breast cancer patients carries an inherited genetic variant linked to cancer risk, with the majority of these variants occurring outside the well-known BRCA1 and BRCA2 genes.

The findings underscore the urgent need to re-examine current genetic testing strategies in India, which continue to rely heavily on BRCA-only or hotspot-based testing.

By providing a high-resolution genetic baseline for Indian breast cancer, this work lays critical groundwork for ancestry-aware precision oncology, family-based risk reduction strategies and improved chemotherapy safety. The research team noted that expanding such studies nationally will be essential to developing genomic policies tailored to India’s unique population structure and disease burden.

The findings were published in BMC Cancer (https://doi.org/10.1186/s12885-025-15360-w), a prestigious, high‑impact specialist journal in oncology.

The Research Paper was co-authored by John Peter, Jayalakshmi Jothi, Avrajit Chakraborty, S Mahalingam from 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 Department of Oncology, Kumaran Hospital, Chennai, and Selvi Radhakrishnan from Chennai Breast Centre. Chennai.

The study analysed germline DNA from 479 unselected breast cancer patients whose samples were sourced from the National Cancer Tissue Biobank at IIT Madras. It represents one of the most comprehensive hereditary breast cancer datasets generated in the country. The study is now part of the Bharat Cancer Genome Atlas, India’s first and largest open-source cancer genome data resource.

Elaborating on the key findings, Lead Author Prof. S. Mahalingam, Head, National Cancer Tissue Biobank, IIT Madras, 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 such as Marfan syndrome, malignant hyperthermia susceptibility, inherited cardiac arrhythmias and familial hypercholesterolaemia. About 8 percent were carriers of recessive metabolic and genetic disorders, including biotinidase deficiency and Wilson disease. These findings demonstrate how comprehensive germline sequencing can uncover clinically meaningful information beyond cancer predisposition.”

Further, Dr Bani Jolly, said, “This 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 frequency 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.”

THE STUDY

The 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.

The researchers also 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 with highly 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, demonstrating that the inherited landscape of breast cancer risk in India is far more complex than previously appreciated.

The researchers 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 seen in the Indian cohort, highlighting strong regional and population-driven differences.