What Happened
- Researchers from IIT Madras (in collaboration with Karkinos Healthcare) have found that 1 in 4 (24.6%) Indian breast cancer patients carries an inherited pathogenic or likely pathogenic genetic variant linked to cancer risk.
- The study analysed germline DNA from 479 patients using samples from the National Cancer Tissue Biobank at IIT Madras — one of the country's largest hereditary breast cancer datasets.
- Critically, only 8.35% of patients had variants in BRCA1 or BRCA2 — the genes most commonly tested in clinical practice — while 11.9% had pathogenic variants in other genes involved in the homologous recombination repair (HRR) pathway.
- Across all positive findings, 67% occurred in non-BRCA genes including MLH1, NF1, TP53, and RB1, revealing that India's hereditary breast cancer landscape is far broader and more complex than BRCA-focused testing can capture.
- Over 21% of patients also carried actionable variants in non-cancer genes associated with Marfan syndrome, malignant hyperthermia, inherited cardiac arrhythmias, and familial hypercholesterolaemia — underscoring the value of comprehensive genetic testing.
- The study, published in BMC Cancer, argues for a shift from BRCA-only to multi-gene panel or exome-based germline testing in India's clinical practice.
Static Topic Bridges
BRCA Genes and Hereditary Breast Cancer: The Standard Framework
BRCA1 and BRCA2 are tumour suppressor genes whose primary role is repairing DNA double-strand breaks via the homologous recombination repair (HRR) pathway. Inherited (germline) mutations in these genes dramatically elevate lifetime breast and ovarian cancer risk. BRCA testing became the global standard for hereditary breast cancer risk assessment after the identification of these genes in the 1990s.
- Germline BRCA1 mutations confer a lifetime breast cancer risk of ≥60% and ovarian cancer risk of ≥40% (by age 70).
- BRCA2-associated breast cancers tend to be oestrogen-receptor positive; BRCA1-associated cancers are typically triple-negative breast cancer (TNBC).
- BRCA1/2-mutant cancers are sensitive to PARP inhibitors — a class of targeted therapy now approved for breast, ovarian, pancreatic, and prostate cancers.
- Standard clinical BRCA testing in India is done in urban private hospitals; access in tier-2 and rural settings is limited.
Connection to this news: The IIT Madras study shows that restricting testing to BRCA1/2 misses 67% of all inherited risk variants in Indian breast cancer patients — making the standard framework clinically inadequate for the Indian population.
Homologous Recombination Repair (HRR) Pathway and Cancer Risk
Homologous recombination (HR) is a critical DNA repair mechanism that fixes double-strand DNA breaks using an identical DNA template (the sister chromatid). BRCA1 and BRCA2 are the most well-known components of this pathway, but many other genes — PALB2, CHEK2, ATM, RAD51C, BRIP1, etc. — are also essential. Mutations in any of these genes can cause HR deficiency, increasing genomic instability and cancer risk.
- The HR pathway involves a cascade: BRCA1 is recruited to DNA break sites by ATM, then BRCA2 (with PALB2) loads RAD51 onto the damaged strand for template-based repair.
- Genes like MLH1, NF1, TP53, and RB1 — identified as mutated in the IIT Madras study — serve overlapping roles in genome stability, cell cycle checkpoints, and tumour suppression.
- HR-deficient tumours are often sensitive to platinum-based chemotherapy in addition to PARP inhibitors.
- Multi-gene panel testing (testing 15–40 genes simultaneously) is increasingly standard in Western clinical practice but remains rare in India.
Connection to this news: The 11.9% rate of HRR pathway variants (beyond BRCA) in the IIT Madras cohort, versus 8.35% for BRCA alone, directly demonstrates that non-BRCA HRR gene mutations are numerically more important in Indian breast cancer patients — reshaping the evidence base for clinical testing protocols.
Genomics and Precision Oncology in India
Precision oncology uses individual tumour and germline genetic profiles to guide treatment decisions — selecting therapies most likely to work for that patient's specific cancer biology. India is at an early stage of integrating precision oncology into mainstream clinical practice; most treatment decisions are still made on clinical and histopathological criteria alone.
- Bharat Genome Atlas (BGA) is India's flagship initiative to map the genomic landscape of cancers in the Indian population, recognising that Western genomic databases may not accurately represent Indian genetic variants.
- IIT Madras's National Cancer Tissue Biobank is a key resource for such population-specific genomic research.
- India's cancer burden: approximately 1.46 million new cancer cases annually (2022); breast cancer is the most common cancer in women, accounting for ~28% of all female cancers.
- Germline testing is distinct from somatic tumour testing: germline variants are inherited and present in every cell; somatic mutations are acquired in the tumour itself.
Connection to this news: The IIT Madras study contributes directly to the Bharat Genome Atlas mission — building India-specific genomic evidence to guide clinical practice rather than extrapolating from Western population data.
Genetic Counselling and Cascade Testing: Public Health Implications
When a hereditary cancer-risk variant is identified in a patient, their first-degree relatives (parents, siblings, children) have a 50% probability of carrying the same variant — making cascade genetic testing of family members a critical public health intervention. This can enable preventive surgery (prophylactic mastectomy), enhanced surveillance, or targeted treatment.
- Genetic counselling is a specialist clinical service that helps patients and families understand genetic test results and their implications.
- In India, the number of certified genetic counsellors is estimated at fewer than 1,000 — grossly inadequate for a population of 1.4 billion.
- The IIT Madras study's finding that 21% of patients carried actionable variants in non-cancer genes (cardiac, connective tissue disorders) means cascade testing could prevent non-cancer deaths too.
- Cost is a major barrier: comprehensive multi-gene panel testing currently costs ₹15,000–50,000+ in India; lack of insurance coverage limits access.
Connection to this news: The study makes a compelling case for integrating broader germline testing into India's National Cancer Control Programme, expanding beyond BRCA to multi-gene panels — with clear implications for public health policy.
Key Facts & Data
- Study: IIT Madras + Karkinos Healthcare, published in BMC Cancer
- Cohort: 479 breast cancer patients, National Cancer Tissue Biobank, IIT Madras
- Key finding: 24.6% (1 in 4) carry pathogenic/likely pathogenic germline variants
- BRCA1/2 variants: 8.35% of patients
- Non-BRCA HRR pathway variants: 11.9% of patients
- Non-BRCA variants as share of all positive findings: 67%
- Genes identified beyond BRCA: MLH1, NF1, TP53, RB1 among others
- Actionable non-cancer gene variants: >21% of patients (Marfan syndrome, cardiac arrhythmias, etc.)
- India cancer burden: ~1.46 million new cases/year; breast cancer = ~28% of female cancers