Historically, the understanding of breast cancer focused on environmental factors, lifestyle, and trauma. For centuries, treatment centered on surgery, based on the theory that cancer was a localized affliction curable by complete physical removal of the tumor. This surgical-centric view, exemplified by procedures like the radical mastectomy, dominated medical practice and focused on the visible disease rather than its origin.
Observations of cancer running in families, dating back to the mid-19th century, offered a counterpoint. Clinicians noted the tendency for breast cancer to affect multiple relatives across generations, hinting at an inherited predisposition. This familial pattern suggested that some individuals might be born with an inherent, increased susceptibility to the disease. The search for a molecular explanation for this hereditary risk became a major focus of scientific investigation.
The Discovery of BRCA1
The first gene definitively associated with an inherited, high risk of breast cancer was BRCA1, which stands for Breast Cancer gene 1. A research team initially identified the gene’s chromosomal location in 1990, marking a breakthrough in linking familial risk to a specific molecular component. The international scientific effort to precisely pinpoint and clone the gene culminated in its official identification in 1994.
The gene was found on the long arm of human chromosome 17, specifically at position 17q21. This location was determined through extensive genetic linkage analysis, which tracked the inheritance of genetic markers alongside the cancer predisposition in high-risk families. The naming of BRCA1 confirmed that inherited breast cancer could be traced to a specific molecular defect, providing the first concrete target for managing hereditary risk.
The Gene’s Role in Cellular Repair
The healthy, non-mutated version of the BRCA1 gene is classified as a tumor suppressor gene, playing a protective role in the body. Tumor suppressor proteins prevent cells from growing and dividing too rapidly. The BRCA1 protein acts as a caretaker for the cell’s genetic material, working within the cell nucleus to maintain genome stability.
Its primary function is in the DNA damage response pathway, specifically repairing double-strand DNA breaks, which are particularly dangerous forms of damage. The protein is involved in homologous recombination, a highly accurate repair process that uses an undamaged copy of the DNA as a template. This mechanism prevents the accumulation of errors that can lead to uncontrolled cell division and cancer formation.
When an individual inherits a harmful mutation in BRCA1, the resulting protein is often non-functional or abnormally shortened. This genetic defect means the cell loses one of its most important mechanisms for fixing severe DNA damage. With the loss of this critical repair function, DNA errors accumulate more rapidly, destabilizing the genome and significantly increasing the likelihood of a cell transforming into a cancerous tumor.
Clinical Applications of Genetic Risk Assessment
The discovery of BRCA1 quickly led to genetic testing, allowing individuals to determine if they carry a pathogenic variant. Testing is typically recommended for people with a personal or family history suggestive of hereditary cancer, such as a breast cancer diagnosis before age 50 or a known BRCA mutation in a relative. The test analyzes a sample of blood or saliva to look for specific alterations in the gene’s DNA sequence.
Test results are generally reported as positive, negative, or a variant of uncertain significance (VUS). A positive result indicates the presence of a harmful mutation, confirming a significantly increased lifetime cancer risk. Women with an inherited BRCA1 mutation face a high lifetime risk of developing breast cancer, with estimates ranging between 60% and 80% in some studies, compared to about 13% for the general population.
The knowledge of a positive BRCA1 mutation allows for proactive risk management strategies. Preventative measures include enhanced cancer surveillance, such as alternating mammograms with magnetic resonance imaging (MRI) scans for earlier detection. Individuals may opt for prophylactic surgeries, such as a preventative mastectomy or the removal of the ovaries and fallopian tubes, which drastically reduce the risk of developing breast and ovarian cancers. Chemoprevention, using certain medications to lower cancer risk, is another management option.
Expanding the Genetic Landscape
While BRCA1 was the first gene identified, evidence suggested other genes were also involved in hereditary breast cancer. Just a year later, BRCA2 (Breast Cancer gene 2) was discovered in 1995 and localized on chromosome 13. BRCA2 also functions as a tumor suppressor involved in DNA repair, similar to BRCA1. However, mutations in BRCA2 carry slightly different risk profiles and are associated with a greater risk of male breast cancer and pancreatic cancer.
The current landscape of genetic risk assessment now includes many other genes beyond the two BRCA genes, reflecting the complexity of inherited cancer risk. Genes such as PALB2, which works directly with BRCA2 in DNA repair, and CHEK2, a tumor suppressor involved in cell cycle control, are routinely included in multi-gene panel tests. The discovery of BRCA1 established the precedent for gene-based cancer risk assessment, leading to the broader genetic screening panels used in clinical practice today.