CHENNAI: In one of the largest breast cancer genomics studies conducted in the country, researchers from the Indian Institute of Technology Madras (IIT-M) and Karkinos Healthcare have found that nearly one in four Indian breast cancer patients carry an inherited cancer-linked genetic variant, with most of these alterations occurring outside the widely tested BRCA1 and BRCA2 genes.
The findings, published in the peer-reviewed journal BMC Cancer, underscore the urgent need to move beyond BRCA-only testing and adopt broader multi-gene or exome-based germline screening tailored to India’s population.
The study analysed germline DNA from 479 unselected breast cancer patients, with samples sourced from the National Cancer Tissue Biobank at IIT-M. It now forms part of the Bharat Cancer Genome Atlas, India's largest open-source cancer genome data resource.
Researchers 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, and findings were compared with global datasets to identify Indian- and South Asian-specific patterns.
The study found that 24.6 percent of patients carried at least one pathogenic or likely pathogenic variant. While 8.35 percent had BRCA1 or BRCA2 variants, a larger proportion – 11.9 percent – carried inherited mutations in other homologous recombination repair genes. Overall, 67 percent of all positive findings were in non-BRCA genes such as MLH1, NF1, TP53 and RB1.
Lead author S Mahalingam, head, National Cancer Tissue Biobank at IIT-M, said that the findings have direct implications for clinical practice and public health policy. “With around 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. There is also a clear need for India- and South Asia-specific variant databases to ensure accurate risk assessment,” he said.
The study makes a compelling case for shifting from BRCA-only testing to broader multi-gene panel or exome-based germline testing in India. There is also a clear need for India- and South Asia-specific variant databases to ensure accurate risk assessment
- S Mahalingam, head, National Cancer Tissue Biobank at IIT-M
The research also revealed clinically significant secondary findings. More than 21percent of patients carried actionable variants in non-cancer genes linked to conditions such as Marfan syndrome, malignant hyperthermia susceptibility, inherited cardiac arrhythmias and familial hypercholesterolaemia. Around 8% were carriers of recessive disorders including biotinidase deficiency and Wilson disease.
Dr John Peter, first author of the study, said, “A comprehensive germline sequencing can uncover health risks beyond cancer predisposition, enabling preventive interventions for families.”
The team further identified pharmacogenomic variants affecting chemotherapy safety. Clinically significant DPYD variants associated with severe toxicity to fluoropyrimidine drugs such as 5-FU and capecitabine were detected at measurable frequency. Dr Bani Jolly said, “The findings support strong consideration for routine DPYD genotyping before initiating chemotherapy.”
The study also identified ancestry-specific variants, including an India-enriched BRCA1 c.68-69delAG mutation and potential India-specific alterations in the RECQL gene, highlighting population-driven differences in genetic risk.
Researchers said that expanding such genomic studies nationally would be critical to shaping cancer guidelines that reflect India's unique genetic landscape and disease burden.