Study on Breast Cancer Genetic Risk

Why in News?

Recently, a study conducted and published by IIT-M reported that 1 in 4 Indian breast cancer patients carries inherited genetic risk variants, most of them outside the well-known BRCA1/2 genes.

• Cancer – It is a disease caused by uncontrolled cell division due to genetic mutations that disrupt normal growth-regulating genes.
• These mutations may be –
  • Somatic – Acquired during lifetime.
  • Germline – Inherited and present in all cells (with increase lifetime risk).
• Breast Cancer – It is a disease where abnormal cells in the breast grow uncontrollably.

India reports around 1.9 lakh new breast cancer cases annually, and over 10% of breast cancers are linked to inherited germline mutations.

• Types – Most common are
  • Invasive Ductal Carcinoma (starts in ducts) and
  • Invasive Lobular Carcinoma (starts in glands).
• Other types - Ductal Carcinoma in Situ (non-invasive) and less common inflammatory or Paget's disease.
• Key Symptoms – Includes a new lump in the breast/armpit, skin changes like dimpling (like small pits), or nipple discharge.
• Key Genetic Risk Factors – BRCA1 and BRCA2 – They normally help repair serious DNA damage through a process called homologous recombination repair (HRR).
• When these genes are mutated, the body cannot properly fix broken DNA, leading to unstable cells that can turn cancerous.
• Other DNA Repair Genes – Genes like ATM, PALB2 and CHEK2 also help repair damaged DNA.
• If they do not function properly, DNA errors build up over time, increasing cancer risk.
• Tumour Suppressor and Cell-Control Genes – Genes such as MLH1, NF1, TP53, and RB1 normally control cell growth, repair DNA mistakes, and remove damaged cells.
• When they’re defective and fail to repair DNA properly, they avoid natural cell death, ultimately leading to cancer development.
• Treatment – Surgery – Ranges from removing the tumour to removing the entire breast.
• Radiation Therapy – High-energy rays are used to kill cancer cells.
• Systemic Therapy – Includes chemotherapy, hormone therapy, and targeted therapies (e.g., HER2 inhibitors). 

Key Findings of the Study

• Inherited Risk – Study found that about 1 in 4 breast cancer patients (24.6%) carried an inherited genetic change that increases cancer risk
• Risks beyond BRCA Genes – Although BRCA1 and BRCA2 are widely known breast cancer genes, only 8.35% of patients had mutations in these genes, showing that most inherited risk (67%) was due to other genes beyond BRCA.
• Important Non-BRCA Genes Were Identified – Several other genes were found to be commonly affected:
  • MLH1 (3.5%)
  • NF1 (2.7%)
  • TP53 (1.5%)
  • RB1 (1.5%)
• This means breast cancer risk in Indian patients is more genetically complex than previously believed.

The Bharat Cancer Genome Atlas (BCGA), led by IIT Madras, is an open-access database that maps the unique genetic patterns of cancers in Indians, aims to improve diagnosis and treatment through precision medicine.

• Role of DNA Repair Genes – Many mutations were found in genes involved in the Homologous Recombination Repair (HRR) pathway.
  • HRR normally helps repair damaged DNA. When this repair system fails, cells accumulate damage and can turn cancerous.
• Unique or Rare Globally – The study found 31 HRR variants and 41 other variants that were absent in global databases but present in Indian patients.
• Hence, some genetic risks may be specific or more common in the Indian population.
• RECQL, an Emerging Risk Gene – Two RECQL gene variants were found in 1.7% of patients.
• Some of these showed higher frequency in South Asians, indicating possible population-specific risk patterns.
• Testing shift – Need to re-examine current genetic testing strategies in India, which continue to rely heavily on BRCA-only.
  • Shift to broader multi-gene panel or exome-based germline testing.

Reference

TH | New Breast Cancer Genetic Risk Study